| 331. |
- Travaglini, Lorena, et al.
(författare)
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Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders
- 2013
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 21:10, s. 8-1074
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Tidskriftsartikel (refereegranskat)abstract
- Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.
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| 332. |
- Trentin, Danielle S, et al.
(författare)
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Natural green coating inhibits adhesion of clinically important bacteria
- 2015
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 5, s. 8287-
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Tidskriftsartikel (refereegranskat)abstract
- Despite many advances, biomaterial-associated infections continue to be a major clinical problem. In order to minimize bacterial adhesion, material surface modifications are currently being investigated and natural products possess large potential for the design of innovative surface coatings. We report the bioguided phytochemical investigation of Pityrocarpa moniliformis and the characterization of tannins by mass spectrometry. It was demonstrated that B-type linked proanthocyanidins-coated surfaces, here termed Green coatings, reduced Gram-positive bacterial adhesion and supported mammalian cell spreading. The proposed mechanism of bacterial attachment inhibition is based on electrostatic repulsion, high hydrophilicity and the steric hindrance provided by the coating that blocks bacterium-substratum interactions. This work shows the applicability of a prototype Green-coated surface that aims to promote necessary mammalian tissue compatibility, while reducing bacterial colonization.
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| 333. |
- Van Bulck, Liesbet, et al.
(författare)
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Rationale, design and methodology of APPROACH-IS II: International study of patient-reported outcomes and frailty phenotyping in adults with congenital heart disease.
- 2022
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Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 363, s. 30-39
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, patient-reported outcomes (PROs) have received increasing prominence in cardiovascular research and clinical care. An understanding of the variability and global experience of PROs in adults with congenital heart disease (CHD), however, is still lacking. Moreover, information on epidemiological characteristics and the frailty phenotype of older adults with CHD is minimal. The APPROACH-IS II study was established to address these knowledge gaps. This paper presents the design and methodology of APPROACH-IS II.APPROACH-IS II is a cross-sectional global multicentric study that includes Part 1 (assessing PROs) and Part 2 (investigating the frailty phenotype of older adults). With 53 participating centers, located in 32 countries across six continents, the aim is to enroll 8000 patients with CHD. In Part 1, self-report surveys are used to collect data on PROs (e.g., quality of life, perceived health, depressive symptoms, autonomy support), and explanatory variables (e.g., social support, stigma, illness identity, empowerment). In Part 2, the cognitive functioning and frailty phenotype of older adults are measured using validated assessments.APPROACH-IS II will generate a rich dataset representing the international experience of individuals in adult CHD care. The results of this project will provide a global view of PROs and the frailty phenotype of adults with CHD and will thereby address important knowledge gaps. Undoubtedly, the project will contribute to the overarching aim of improving optimal living and care provision for adults with CHD.
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| 334. |
- Vanzella, Eros, et al.
(författare)
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JWST/NIRCam Probes Young Star Clusters in the Reionization Era Sunrise Arc
- 2023
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 945:1
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Tidskriftsartikel (refereegranskat)abstract
- Star cluster formation in the early universe and its contribution to reionization remains largely unconstrained to date. Here we present JWST/NIRCam imaging of the most highly magnified galaxy known at z ∼ 6, the Sunrise arc. We identify six young massive star clusters (YMCs) with measured radii spanning from ∼20 down to ∼1 pc (corrected for lensing magnification), estimated stellar masses of ∼106–7 M⊙, and ages of 1–30 Myr based on SED fitting to photometry measured in eight filters extending to rest frame 7000 Å. The resulting stellar mass surface densities are higher than 1000 M⊙ pc−2 (up to a few 105 M⊙ pc−2), and their inferred dynamical ages qualify the majority of these systems as gravitationally bound stellar clusters. The star cluster ages map the progression of star formation along the arc, with two evolved systems (≳10 Myr old) followed by very young clusters. The youngest stellar clusters (<5 Myr) show evidence of prominent Hβ+[O ııı] emission based on photometry with equivalent widths larger than >1000 Å rest frame and are hosted in a 200 pc sized star-forming complex. Such a region dominates the ionizing photon production with a high efficiency log(ξion [Hz erg-1]~25.7 . A significant fraction of the recently formed stellar mass of the galaxy (10%–30%) occurred in these YMCs. We speculate that such sources of ionizing radiation boost the ionizing photon production efficiency, which eventually carves ionized channels that might favor the escape of Lyman continuum radiation. The survival of some of the clusters would make them the progenitors of massive and relatively metal-poor globular clusters in the local universe.
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| 335. |
- Viswanath, Gayathri, 1992-, et al.
(författare)
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Exoplanet Accretion Monitoring Spectroscopic Survey (ENTROPY).I — Evidence for magnetospheric accretion in the young isolated planetary-mass object 2MASS J11151597+1937266
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Accretion among planetary mass companions is a poorly understood phenomenon, mainly due to the lack of observational studies that shed light on the process. Detection of emission lines from accreting gas giants facilitate detailed investigations into their formation mechanisms. This work adds another young, sub-stellar candidate to the sample of few planetary-mass objects with observed emission lines − an isolated L2ϒ dwarf 2MASS J11151597+1937266 with a mass between 7 and 21 MJup and an age of 5−45 Myr, located at 45.49±2.14 pc. We obtained the first high-resolution (R~50,000) spectrum of the target with VLT/UVES, an echelle spectrograph operating in the near-UV to visible wavelengths (3200−6800 Å). We report on several resolved H I (H3−H7) and He I emission lines (λ5875.6 Å ) in the spectrum. Based on the asymmetric line profiles of Hα and Hβ, the 10% width of Hα emission (198±5 km s-1), tentative He I emission at 6678 Å and indications of a disk from MIR excess, we confirm ongoing accretion at this object. We revise the physical parameters of the target based on the more accurate Gaia parallax-based distance measurement and derive a mass accretion rate of MJup yr-1 for 2MASS J11151597+1937266 based on the HI line luminosities using planetary scaling relations for Lline‾Lacc. Analysis of the observed H I profiles within the framework of planet-surface shock model implies a pre-shock gas velocity of v0= km s-1 and a pre-shock density of n0=1013 cm-3. The line-emitting area of the planet predicted from planet-surface shock model is very small (~0.09%), and points to a shock at the base of a magnetospherically induced funnel. The Hα profile exhibits a much stronger flux than predicted by the best-fitting model to the rest of the H I profiles, indicating that another mechanism than shock emission contributes to, or even dominates, the Hα emission. On comparison of line fluxes and mass accretion rate from this UVES epoch with those from archival low-resolution SDSS DR9 and DR12 spectra, we cannot exclude variability in accretion at 2MASS J11151597+1937266.
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| 336. |
- Wagh, Rucha, et al.
(författare)
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Twins in Guinea-Bissau have a 'thin-fat' body composition compared to singletons
- 2022
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Ingår i: Journal of Developmental Origins of Health and Disease. - 2040-1744. ; 13:6, s. 787-793
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Tidskriftsartikel (refereegranskat)abstract
- The 'thrifty phenotype' hypothesis proposed that fetal undernutrition increases risk of diabetes in later life. Undernourished low birthweight Indian babies are paradoxically more adipose compared to well-nourished European babies, and are at higher risk of diabetes in later life. Twin pregnancies are an example of in utero growth restrictive environment due to shared maternal nutrition. There are few studies of body composition in twins. We performed secondary analysis of anthropometric body composition of twins and singletons in Guinea-Bissau, an economically deprived African country. Anthropometric data were available on 7-34 year-old twins (n = 209, 97 males) and singletons (n = 182, 86 males) in the Guinea-Bissau Twin Registry at the Bandim Health Project. Twins had lower birthweight (2420 vs 3100 g, p < 0.001); and at follow-up, lower height (HAZ mean Z-score difference, -0.21, p = 0.055), weight (WAZ -0.73, p = 0.024) and BMI (BAZ -0.22, p = 0.079) compared to singletons but higher adiposity (skinfolds: +0.33 SD, p = 0.001). Twins also had higher fasting (+0.38 SD, p < 0.001) and 2-hour OGTT glucose concentrations (+0.29 SD, p < 0.05). Linear mixed-effect model accounting for intrapair correlations and interactions confirmed that twins were thinner but fatter across the age range. Data on maternal morbidity and prematurity were not available in this cohort. African populations are known to have a muscular (less adipose) body composition. Demonstration of a thin-fat phenotype in twins in a low socio-economic African country supports the thesis that it could be a manifestation of early life undernutrition and not exclusive to Indians. This phenotype could increase risk of diabetes and related conditions.
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| 337. |
- Wallentin, Lars, et al.
(författare)
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Lipoprotein-Associated Phospholipase A(2) Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease
- 2016
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Ingår i: Journal of the American Heart Association. - 2047-9980 .- 2047-9980. ; 5:6
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Tidskriftsartikel (refereegranskat)abstract
- Background - We evaluated lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp-PLA(2) inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial.Methods and Results - Plasma Lp-PLA(2) activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp-PLA(2) activity levels and outcomes. At baseline, the median Lp-PLA(2) level was 172.4 mu mol/min per liter (interquartile range 143.1-204.2 mu mol/min per liter). Comparing the highest and lowest Lp-PLA(2) quartile groups, the hazard ratios were 1.50 (95% CI 1.23-1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29-2.93) for hospitalization for heart failure, 1.42 (1.07-1.89) for cardiovascular death, and 1.37 (1.03-1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a approximate to 65% persistent reduction in median Lp-PLA(2) activity. There were no associations between on-treatment Lp-PLA(2) activity or changes of Lp-PLA(2) activity and outcomes, and there were no significant interactions between baseline and on-treatment Lp-PLA(2) activity or changes in Lp-PLA(2) activity levels and the effects of darapladib on outcomes.Conclusions - Although high Lp-PLA(2) activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp-PLA(2) activity by approximate to 65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp-PLA(2) activity.
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| 338. |
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| 339. |
- Wang, Gang, et al.
(författare)
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Tumour extracellular vesicles and particles induce liver metabolic dysfunction
- 2023
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Ingår i: Nature. - : NATURE PORTFOLIO. - 0028-0836 .- 1476-4687. ; 618:7964, s. 374-382
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Tidskriftsartikel (refereegranskat)abstract
- Cancer alters the function of multiple organs beyond those targeted by metastasis(1,2). Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.
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| 340. |
- Wesolowska, Paulina, et al.
(författare)
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Testing the methodology for a dosimetric end-to-end audit of IMRT/VMAT: results of IAEA multicentre and national studies
- 2019
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Ingår i: Acta Oncologica. - : TAYLOR & FRANCIS LTD. - 0284-186X .- 1651-226X. ; 58:12, s. 1731-1739
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Within an International Atomic Energy Agency (IAEA) co-ordinated research project (CRP), a remote end-to-end dosimetric quality audit for intensity modulated radiation therapy (IMRT)/ volumetric arc therapy (VMAT) was developed to verify the radiotherapy chain including imaging, treatment planning and dose delivery. The methodology as well as the results obtained in a multicentre pilot study and national trial runs conducted in close cooperation with dosimetry audit networks (DANs) of IAEA Member States are presented. Material and methods: A solid polystyrene phantom containing a dosimetry insert with an irregular solid water planning target volume (PTV) and organ at risk (OAR) was designed for this audit. The insert can be preloaded with radiochromic film and four thermoluminescent dosimeters (TLDs). For the audit, radiotherapy centres were asked to scan the phantom, contour the structures, create an IMRT/VMAT treatment plan and irradiate the phantom. The dose prescription was to deliver 4 Gy to the PTV in two fractions and to limit the OAR dose to a maximum of 2.8 Gy. The TLD measured doses and film measured dose distributions were compared with the TPS calculations. Results: Sixteen hospitals from 13 countries and 64 hospitals from 6 countries participated in the multicenter pilot study and in the national runs, respectively. The TLD results for the PTV were all within +/- 5% acceptance limit for the multicentre pilot study, whereas for national runs, 17 participants failed to meet this criterion. All measured doses in the OAR were below the treatment planning constraint. The film analysis identified seven plans in national runs below the 90% passing rate gamma criteria. Conclusion: The results proved that the methodology of the IMRT/VMAT dosimetric end-to-end audit was feasible for its intended purpose, i.e., the phantom design and materials were suitable; the phantom was easy to use and it was robust enough for shipment. Most importantly the audit methodology was capable of identifying suboptimal IMRT/VMAT delivery.
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