| 1. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
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| 3. |
- Li, Constance H., et al.
(författare)
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Sex differences in oncogenic mutational processes
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.
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| 4. |
- Menzel, Annette, et al.
(författare)
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European phenological response to climate change matches the warming pattern
- 2006
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Ingår i: Global Change Biology. - 1354-1013 .- 1365-2486. ; 12:10, s. 1969-1976
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Tidskriftsartikel (refereegranskat)abstract
- Global climate change impacts can already be tracked in many physical and biological systems; in particular, terrestrial ecosystems provide a consistent picture of observed changes. One of the preferred indicators is phenology, the science of natural recurring events, as their recorded dates provide a high-temporal resolution of ongoing changes. Thus, numerous analyses have demonstrated an earlier onset of spring events for mid and higher latitudes and a lengthening of the growing season. However, published single-site or single-species studies are particularly open to suspicion of being biased towards predominantly reporting climate change-induced impacts. No comprehensive study or meta-analysis has so far examined the possible lack of evidence for changes or shifts at sites where no temperature change is observed. We used an enormous systematic phenological network data set of more than 125000 observational series of 542 plant and 19 animal species in 21 European countries (1971-2000). Our results showed that 78% of all leafing, flowering and fruiting records advanced (30% significantly) and only 3% were significantly delayed, whereas the signal of leaf colouring/fall is ambiguous. We conclude that previously published results of phenological changes were not biased by reporting or publication predisposition: the average advance of spring/summer was 2.5 days decade -1 in Europe. Our analysis of 254 mean national time series undoubtedly demonstrates that species' phenology is responsive to temperature of the preceding months (mean advance of spring/summer by 2.5 days °C -1, delay of leaf colouring and fall by 1.0 day °C -1). The pattern of observed change in spring efficiently matches measured national warming across 19 European countries (correlation coefficient r = -0.69, P < 0.001).
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| 5. |
- Sikoparija, B., et al.
(författare)
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Spatial and temporal variations in airborne Ambrosia pollen in Europe
- 2017
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Ingår i: Aerobiologia. - : Springer Science and Business Media LLC. - 0393-5965 .- 1573-3025. ; 33, s. 181-189
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Tidskriftsartikel (refereegranskat)abstract
- © 2016, The Author(s). The European Commission Cooperation in Science and Technology (COST) Action FA1203 “SMARTER” aims to make recommendations for the sustainable management of Ambrosia across Europe and for monitoring its efficiency and cost-effectiveness. The goal of the present study is to provide a baseline for spatial and temporal variations in airborne Ambrosia pollen in Europe that can be used for the management and evaluation of this noxious plant. The study covers the full range of Ambrosia artemisiifolia L. distribution over Europe (39°N–60°N; 2°W–45°E). Airborne Ambrosia pollen data for the principal flowering period of Ambrosia (August–September) recorded during a 10-year period (2004–2013) were obtained from 242 monitoring sites. The mean sum of daily average airborne Ambrosia pollen and the number of days that Ambrosia pollen was recorded in the air were analysed. The mean and standard deviation (SD) were calculated regardless of the number of years included in the study period, while trends are based on those time series with 8 or more years of data. Trends were considered significant at p<0.05. There were few significant trends in the magnitude and frequency of atmospheric Ambrosia pollen (only 8% for the mean sum of daily average Ambrosia pollen concentrations and 14% for the mean number of days Ambrosia pollen were recorded in the air). The direction of any trends varied locally and reflected changes in sources of the pollen, either in size or in distance from the monitoring station. Pollen monitoring is important for providing an early warning of the expansion of this invasive and noxious plant.
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| 6. |
- Gozdzik, W, et al.
(författare)
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Beneficial effects of inhaled nitric oxide with intravenous steroid in an ischemia-reperfusion model involving aortic clamping
- 2018
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Ingår i: International journal of immunopathology and pharmacology. - : SAGE Publications. - 2058-7384. ; 3132, s. 394632017751486-
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Tidskriftsartikel (refereegranskat)abstract
- This study evaluated the effects of inhaled nitric oxide (iNO) therapy combined with intravenous (IV) corticosteroids on hemodynamics, selected cytokines, and kidney messenger RNA toll-like receptor 4 (mRNA TLR4) expression in ischemia–reperfusion injury animal model. The primary endpoint was the evaluation of circulatory, respiratory, and renal function over time. We also investigated the profile of selected cytokines and high-mobility group box 1 (HMGB1) protein, as well as renal mRNA TLR4 activation determined by quantitative real-time polymerase chain reaction analysis. Pigs (n = 19) under sevoflurane AnaConDa anesthesia/sedation were randomized and subjected to abdominal laparotomy and alternatively suprarenal aortic cross-clamping (SRACC) for 90 min or sham surgery: Group 1 (n = 8) iNO (80 ppm) + IV corticosteroids (25 mg ×3) started 30 min before SRACC and continued 2 h after SRACC release, followed with decreased iNO (30 ppm) until the end of observation, Group 2 (n = 8) 90 min SRACC, Group 3 (n = 3)—sham surgery. Renal biopsies were sampled 1 hr before SRACC and at 3 and 20 h after SRACC release. Aortic clamping increased TLR4 mRNA expression in ischemic kidneys, but significant changes were recorded only in the control group ( P = 0.016). Treatment with iNO and hydrocortisone reduced TLR4 mRNA expression to pre-ischemic conditions, and the difference observed in mRNA expression was significant between control and treatment group after 3 h ( P = 0.042). Moreover, animals subjected to treatment with iNO and hydrocortisone displayed an attenuated systemic inflammatory response and lowered pulmonary vascular resistance plus increased oxygen delivery. The results indicated that iNO therapy combined with IV corticosteroids improved central and systemic hemodynamics, oxygen delivery, and diminished the systemic inflammatory response and renal mRNA TLR4 expression.
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| 7. |
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| 8. |
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| 9. |
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| 11. |
- Kübler, André, et al.
(författare)
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Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation.
- 2015
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 235:3, s. 431-444
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Tidskriftsartikel (refereegranskat)abstract
- Active tuberculosis (TB) often presents with advanced pulmonary disease, including irreversible lung damage and cavities. Cavitary pathology contributes to antibiotic failure, transmission, morbidity and mortality. Matrix metalloproteinases (MMPs), in particular MMP-1 are implicated in TB pathogenesis. We explored the mechanisms relating MMP/TIMP imbalance to cavity formation in a modified rabbit model of cavitary TB. Our model results in consistent progression of consolidation to human-like cavities (100% by day 28) with resultant bacillary burdens (>10(7) CFU/g) far greater than those found in matched granulomatous tissue (10(5) CFU/g). Using a novel, breath-hold computerized tomography scanning and image analysis protocol. We show that cavities develop rapidly from areas of densely consolidated tissue. Radiological change correlated with a decrease in functional lung tissue as estimated by changes in lung density during controlled pulmonary expansion (R(2) =0.6356, p < 0.0001). We demonstrated that the expression of interstitial collagenase (MMP-1) is specifically greater in cavitary compared to granulomatous lesions (p < 0.01), and that TIMP-3 significantly decreases at the cavity surface. Our findings demonstrate that an MMP-1/TIMP imbalance, is associated with the progression of consolidated regions to cavities containing very high bacterial burdens. Our model provided mechanistic insight, correlating with human disease at the pathological, microbiological and molecular levels,. It also provides a strategy to investigate therapeutics in the context of complex TB pathology. We used these findings to predict a MMP/TIMP balance in active TB; and confirmed this in human plasma, revealing the potential of MMP/TIMP levels as key components of a diagnostic matrix aimed at distinguishing active from latent TB (PPV=92.9%; 95%CI 66.1-99.8%, NPV=85.6%; 95%CI 77.0-91.9%).
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| 12. |
- Kubler-Kielb, Joanna, et al.
(författare)
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Oligosaccharide conjugates of Bordetella pertussis and bronchiseptica induce bactericidal antibodies, an addition to pertussis vaccine.
- 2011
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 108:10, s. 4087-92
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Tidskriftsartikel (refereegranskat)abstract
- Pertussis is a highly contagious respiratory disease that is especially dangerous for infants and children. Despite mass vaccination, reported pertussis cases have increased in the United States and other parts of the world, probably because of increased awareness, improved diagnostic means, and waning vaccine-induced immunity among adolescents and adults. Licensed vaccines do not kill the organism directly; the addition of a component inducing bactericidal antibodies would improve vaccine efficacy. We investigated Bordetella pertussis and Bordetella bronchiseptica LPS-derived core oligosaccharide (OS) protein conjugates for their immunogenicity in mice. B. pertussis and B. bronchiseptica core OS were bound to aminooxylated BSA via their terminal Kdo residues. The two conjugates induced similar anti-B. pertussis LPS IgG levels in mice. B. bronchiseptica was investigated because it is easier to grow than B. pertussis. Using B. bronchiseptica genetically modified strains deficient in the O-specific polysaccharide, we isolated fractions of core OS with one to five repeats of the terminal trisaccharide, having at the nonreducing end a GlcNAc or GalNAc, and bound them to BSA at different densities. The highest antibody levels in mice were elicited by conjugates containing an average of 8-17 OS chains per protein and with one repeat of the terminal trisaccharide. Conjugate-induced antisera were bactericidal against B. pertussis, and the titers correlated with ELISA-measured antibody levels (r = 0.74). Such conjugates are easy to prepare and standardize; added to a recombinant pertussis toxoid, they may induce antibacterial and antitoxin immunity.
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| 13. |
- Luna, Brian, et al.
(författare)
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In Vivo Prediction of Tuberculosis-Associated Cavity Formation in Rabbits
- 2015
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Ingår i: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 211:3, s. 481-485
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Tidskriftsartikel (refereegranskat)abstract
- The presence of cavitary lesions in patients with tuberculosis poses a significant clinical concern due to the risk of infectivity and the risk of antibiotic treatment failure. We describe 2 algorithms that use noninvasive positron emission tomography (PET) and computed tomography (CT) to predict the development of cavitary lesions in rabbits. Analysis of the PET region of interest predicted cavitary disease with 100% sensitivity and 76% specificity, and analysis of the CT region of interest predicted cavitary disease with 83.3% sensitivity and 76.9% specificity. Our results show that restricting our analysis to regions with high [(18)F]-fluorodeoxyglucose uptake provided the best combination of sensitivity and specificity.
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| 14. |
- Merheb, J., et al.
(författare)
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Influence of Skeletal and Local Bone Density on Dental Implant Stability in Patients with Osteoporosis
- 2016
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Ingår i: Clinical Implant Dentistry and Related Research. - : Wiley. - 1523-0899 .- 1708-8208. ; 18:2, s. 253-260
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Tidskriftsartikel (refereegranskat)abstract
- Background and PurposeOsteoporosis is a major skeletal disease affecting millions of people worldwide. Recent studies claim that patients with osteoporosis do not have a higher risk of early implant failure compared to non-osteoporotic patients. The aim of this study was to assess the effect of skeletal osteoporosis and local bone density on initial dental implant stability. Materials and MethodsSeventy-three patients were recruited and were assigned (based on a Dual-energy X-ray Absorptiometry scan) to either the osteoporosis (Opr), osteopenia (Opn), or control (C) group. Forty nine of the 73 patients received dental implants and had implant stability measured by means of resonance frequency analysis (RFA) at implant placement and at prosthetic abutment placement. On the computerized tomography scans, the cortical thickness and the bone density (Hounsfield Units) at the sites of implant placement were measured. ResultsAt implant placement, primary stability was on average lower in group Opr (63.310.3 ISQ) than in group Opn (65.3 +/- 7.5 implant stability qutient (ISQ)), and group C (66.7 +/- 8.7 ISQ). At abutment placement, a similar trend was observed: group Opr (66.4 +/- 9.5 ISQ) scored lower than group Opn (70.7 +/- 7.8 ISQ), while the highest average was for group C (72.2 +/- 7.2 ISQ). The difference between groups Opr and C was significant. Implant length and diameter did not have a significant effect on implant stability as measured with RFA. A significant correlation was found between local bone density and implant stability for all regions of interest. ConclusionsImplant stability seems to be influenced by both local and skeletal bone densities. The lower stability scores in patient with skeletal osteoporosis reinforce the recommendations that safe protocols and longer healing times could be recommended when treating those patients with dental implants.
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| 15. |
- Merheb, J., et al.
(författare)
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Relation between Spongy Bone Density in the Maxilla and Skeletal Bone Density
- 2015
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Ingår i: Clinical Implant Dentistry and Related Research. - : Wiley. - 1523-0899 .- 1708-8208. ; 17:6, s. 1180-1187
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Tidskriftsartikel (refereegranskat)abstract
- © 2015 Wiley Periodicals, Inc. Background and Purpose: Osteoporosis is a disease affecting more than 300 million people worldwide and is responsible for numerous medical complications. This study aimed to investigate the relation between skeletal and maxillary bone density. Materials and Methods: Seventy-three patients were recruited and divided between group A (osteoporosis), group B (healthy, control), and group C (osteopenia) on the basis of a dual-energy x-ray absorptiomery (DXA) scan. These patients also received a CT scan on which bone density measurements were performed at five sites: maxilla midline, retromolar tuberosities, incisor, premolars, and molar regions. Results: The bone density was lower in osteoporotic patients compared with the control patients. The bone mineral density (BMD) of the tuberosities showed the strongest correlations with the BMD of the hip and the spine (respectively, r=0.50 and r=0.61). The midline region showed moderate correlations with the hip (r=0.47) and the spine (r=0.46). For potential implant sites, the correlations with the BMD of the hip and spine were, however, small to insignificant. Based on measurements of bone density of the maxilla, it was possible to predict if the patient was osteoporotic or not with a sensitivity of 65% and a specificity of 83%. Conclusions: The maxillary bone density of subjects with osteoporosis is significantly lower than that of healthy patients. Moreover, there is a direct correlation between the density of the skeleton and the density of some sites of the maxilla. Using measurements of maxillary bone density in order to predict skeletal bone density might be a useful tool for the screening of osteoporosis.
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| 16. |
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| 17. |
- SEVERIN, L, et al.
(författare)
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CALCULATED MAGNETIC-PROPERTIES OF URANIUM SULFIDE UNDER PRESSURE
- 1995
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Ingår i: JOURNAL OF MAGNETISM AND MAGNETIC MATERIALS. - : ELSEVIER SCIENCE BV. - 0304-8853. ; 140, s. 1423-1424
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- First principles electronic structure calculations for the itinerant 5f ferromagnet US are presented. At ambient conditions the computed moments agree well with neutron data. As a function of pressure, this magnetization is found to be relatively stable d
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| 18. |
- Sikoparija, B., et al.
(författare)
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A mechanism for long distance transport of Ambrosia pollen from the Pannonian Plain
- 2013
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Ingår i: Agricultural and Forest Meteorology. - : Elsevier BV. - 0168-1923 .- 1873-2240. ; 180, s. 112-117
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Tidskriftsartikel (refereegranskat)abstract
- The pollen grains of ragweed are important aeroallergens that have the potential to be transported long distances through the air. The arrival of ragweed pollen in Nordic countries from the Pannonian Plain can occur when certain conditions are met, which this study aims to describe for the first time. Atmospheric ragweed pollen concentrations were collected at 16 pollen-monitoring sites. Other factors included in the analysis were the overall synoptic weather situation, surface wind speeds, wind direction and temperatures as well as examining regional scale orography and satellite observations. Hot and dry weather in source areas on the Pannonian Plain aid the release of ragweed pollen during the flowering season and result in the deep Planetary Boundary Layers needed to lift the pollen over the Carpathian Mountains to the north. Suitable synoptic conditions are also required for the pollen bearing air masses to move northward. These same conditions produce the jet-effect Kosava and orographic foehn winds that aid the release and dispersal of ragweed pollen and contribute towards its movement into Poland and beyond.
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| 19. |
- Temmerman, A., et al.
(författare)
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A Prospective, Controlled, Multicenter Study to Evaluate the Clinical Outcome of Implant Treatment in Women with Osteoporosis/Osteopenia: 5-Year Results
- 2019
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Ingår i: Journal of Dental Research. - : SAGE Publications. - 0022-0345 .- 1544-0591. ; 98:1, s. 84-90
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Tidskriftsartikel (refereegranskat)abstract
- The impact of osteoporosis on implant treatment is still a matter of debate in the scientific community, as it may possibly lead to higher failure rates. As long-term controlled trials are missing, the aim of this study was to verify the long-term outcome of implants placed in patients with systemic osteoporosis. Postmenopausal women in need of implants underwent bone mineral density measurements in hip and spine, using dual X-ray absorptiometry scans. Based on T-scores, they were divided into 2 groups: group O (osteoporosis group) with a T-score <=-2 or group C (control group) with a T-score of >=-1. Implants were placed in a 2-stage manner and loaded 4 to 8 wk after abutment surgery. Six months after loading and thereafter yearly, clinical and radiographical parameters were assessed. In total, 148 implants were placed in 48 patients (mean age: 67 y [range, 59-83]). Sixty-three implants were placed in 20 patients (group O) and 85 implants in 28 patients (group C). After 5 y, 117 implants (38 in group O and 79 in the group C) in 37 patients were assessed. Cumulative survival rate on an implant level was 96.5% (group O: 91.5%; group C: 100.0% [P < 0.05]) and 95.7% (group O: 89.2%; group C: 100.0% [P > 0.05]) on a patient level. The overall marginal bone-level alterations, after 5 y of loading, were -0.09 +/- 0.78 mm (group O: -0.15 +/- 0.50 mm; group C: -0.06 +/- 0.89 mm) on an implant level and -0.09 +/- 0.54 mm (group O: -0.18 +/- 0.43 mm; group C: 0.06 +/- 0.58 mm) on a patient level (P > 0.05). Oral implant therapy in osteoporotic patients is a reliable treatment option with comparable osseointegration rates, implant survival, and marginal bone-level alterations after 5 y of functional loading (ClinicalTrials.gov NCT00745121).
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| 20. |
- Whichello, Chiara, et al.
(författare)
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Factors and Situations Affecting the Value of Patient Preference Studies : Semi-Structured Interviews in Europe and the US
- 2019
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Patient preference information (PPI) is gaining recognition among the pharmaceutical industry, regulatory authorities, and health technology assessment (HTA) bodies/payers for use in assessments and decision-making along the medical product lifecycle (MPLC). This study aimed to identify factors and situations that influence the value of patient preference studies (PPS) in decision-making along the MPLC according to different stakeholders.Methods: Semi-structured interviews (n = 143) were conducted with six different stakeholder groups (physicians, academics, industry representatives, regulators, HTA/payer representatives, and a combined group of patients, caregivers, and patient representatives) from seven European countries (the United Kingdom, Sweden, Italy, Romania, Germany, France, and the Netherlands) and the United States. Framework analysis was performed using NVivo 11 software.Results: Fifteen factors affecting the value of PPS in the MPLC were identified. These are related to: study organization (expertise, financial resources, study duration, ethics and good practices, patient centeredness), study design (examining patient and/or other preferences, ensuring representativeness, matching method to research question, matching method to MPLC stage, validity and reliability, cognitive burden, patient education, attribute development), and study conduct (patients’ ability/willingness to participate and preference heterogeneity). Three types of situations affecting the use of PPS results were identified (stakeholder acceptance, market situations, and clinical situations).Conclusion: The factors and situation types affecting the value of PPS, as identified in this study, need to be considered when designing and conducting PPS in order to promote the integration of PPI into decision-making along the MPLC.
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