| 1. |
- 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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| 2. |
- Lundstedt, Dan, 1970, et al.
(författare)
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Symptoms 10-17 years after breast cancer radiotherapy data from the randomised SWEBCG91-RT trial
- 2010
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 1879-0887 .- 0167-8140. ; 97:2, s. 281-287
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Tidskriftsartikel (refereegranskat)abstract
- Background: Postoperative radiotherapy decreases the risk for local and improves overall survival in women with breast cancer. We have limited information on radiotherapy-induced symptoms 10-17 years after therapy. Material and methods: Between 1997 and 1997, women with lymph node-negative breast cancer were randomised in a Swedish multi-institutional trial to breast conserving surgery with or without postoperative radiotherapy. In 2007, 10-17 years after randomisation, the group included 422 recurrence-free women. We collected data with a study-specific questionnaire on eight pre-selected symptom groups. Results: Fox six symptom group (oedema in breast or arm, erysipelas, heart symptoms, lung symptoms, rib fractures, and decreased shoulder mobility) we found similar occurrence in both groups. Excess occurence after radiotherapy was observed for pain in the breast or in the skin, reported to occur "occasionally" by 38.1% of survivors having undergone radiotherapy and surgery versus 24.0% of those with surgery alone (absolute difference 14.1%; p = 0.004) and at least once a week by 10.3% of the radiotherapy group versus 1.7% (absolute difference 8.6%; p = 0.001). Daily life and analgesic use did not differ between the groups. Conclusion: Ten to 17 years after postoperative radiotherapy 1 in 12 women had weekly pain that could be attributed to radiotherapy. The symptoms did not significantly affect daily life and thus the reduced risk for local recurrence seems to outweight the risk for long-term symptoms for most women. (C) 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 97 (2010) 281-287
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| 3. |
- Aartsen, M. G., et al.
(författare)
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Observation of High-Energy Astrophysical Neutrinos in Three Years of IceCube Data
- 2014
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 113:10, s. 101101-
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Tidskriftsartikel (refereegranskat)abstract
- A search for high-energy neutrinos interacting within the IceCube detector between 2010 and 2012 provided the first evidence for a high-energy neutrino flux of extraterrestrial origin. Results from an analysis using the same methods with a third year (2012-2013) of data from the complete IceCube detector are consistent with the previously reported astrophysical flux in the 100 TeV-PeV range at the level of 10(-8) GeV cm(-2) s(-1) sr(-1) per flavor and reject a purely atmospheric explanation for the combined three-year data at 5.7 sigma. The data are consistent with expectations for equal fluxes of all three neutrino flavors and with isotropic arrival directions, suggesting either numerous or spatially extended sources. The three-year data set, with a live time of 988 days, contains a total of 37 neutrino candidate events with deposited energies ranging from 30 to 2000 TeV. The 2000-TeV event is the highest-energy neutrino interaction ever observed.
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| 4. |
- Aartsen, M. G., et al.
(författare)
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SEARCHES FOR EXTENDED AND POINT-LIKE NEUTRINO SOURCES WITH FOUR YEARS OF ICECUBE DATA
- 2014
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 796:2, s. 109-
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Tidskriftsartikel (refereegranskat)abstract
- We present results on searches for point-like sources of neutrinos using four years of IceCube data, including the first year of data from the completed 86 string detector. The total livetime of the combined data set is 1373 days. For an E-2 spectrum, the observed 90% C. L. flux upper limits are similar to 10(-12) TeV-1 cm(-2) s(-1) for energies between 1 TeV and 1 PeV in the northern sky and similar to 10(-11) TeV-1 cm(-2) s(-1) for energies between 100 TeV and 100 PeV in the southern sky. This represents a 40% improvement compared to previous publications, resulting from both the additional year of data and the introduction of improved reconstructions. In addition, we present the first results from an all-sky search for extended sources of neutrinos. We update the results of searches for neutrino emission from stacked catalogs of sources and test five new catalogs; two of Galactic supernova remnants and three of active galactic nuclei. In all cases, the data are compatible with the background-only hypothesis, and upper limits on the flux of muon neutrinos are reported for the sources considered.
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| 5. |
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| 6. |
- Alling, Vanja, et al.
(författare)
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Non-conservative behavior of dissolved organic carbon across the Laptev and East Siberian Seas
- 2010
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Ingår i: Global Biogeochemical Cycles. - 0886-6236 .- 1944-9224. ; 24, s. GB4033-
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Tidskriftsartikel (refereegranskat)abstract
- Climate change is expected to have a strong effect on the Eastern Siberian Arctic Shelf (ESAS) region, which includes 40% of the Arctic shelves and comprises the Laptev and East Siberian seas. The largest organic carbon pool, the dissolved organic carbon (DOC), may change significantly due to changes in both riverine inputs and transformation rates; however, the present DOC inventories and transformation patterns are poorly understood. Using samples from the International Siberian Shelf Study 2008, this study examines for the first time DOC removal in Arctic shelf waters with residence times that range from months to years. Removals of up to 10%–20% were found in the Lena River estuary, consistent with earlier studies in this area, where surface waters were shown to have a residence time of approximately 2 months. In contrast, the DOC concentrations showed a strong nonconservative pattern in areas with freshwater residence times of several years. The average losses of DOC were estimated to be 30%–50% during mixing along the shelf, corresponding to a first-order removal rate constant of 0.3 yr−1. These data provide the first observational evidence for losses of DOC in the Arctic shelf seas, and the calculated DOC deficit reflects DOC losses that are higher than recent model estimates for the region. Overall, a large proportion of riverine DOC is removed from the surface waters across the Arctic shelves. Such significant losses must be included in models of the carbon cycle for the Arctic Ocean, especially since the breakdown of terrestrial DOC to CO2 in Arctic shelf seas may constitute a positive feedback mechanism for Arctic climate warming. These data also provide a baseline for considering the effects of future changes in carbon fluxes, as the vast northern carbon-rich permafrost areas draining into the Arctic are affected by global warming.
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| 7. |
- Anderson, Claes, et al.
(författare)
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Habituation to Environmental Enrichment in Captive Sloth Bears - Effect on Stereotypies
- 2010
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Ingår i: Zoo Biology. - Online : Wiley-Liss, Inc.. - 0733-3188 .- 1098-2361. ; 28:6, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- The benefits to captive animals of environmental enrichment (EE) are widely recognized. Few studies have, however, studied how to maximise the effect of EE. One issue with EE programs seems to be habituation to the enrichment device. To study the effect of habituation to EE, 14 captive sloth bears (Melursus ursinus) were subjected to two different EE treatments. Treatment one presented EE (logs with honey containing holes) for five consecutive days, whereas treatment two presented EE on intermittent days for five days. Intermittent presentations tended to reduce habituation toward the EE. Both consecutive and intermittent presentations significantly reduced stereotypies; however, the consecutive presentations had a longer-lasting effect. Explorative behaviors increased in both treatments, consistent with earlier findings that EE increase levels of natural behaviors. Other behaviors were unaffected by the EE presentations. The results show that intermittent presentation of EE objects may secure the interest of the animals, but continuous access to enrichment may be more efficient in reducing stereotypies in the long run.
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| 8. |
- Anderson, Leif G, 1951, et al.
(författare)
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Source and formation of the upper halocline of the Arctic Ocean
- 2013
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Ingår i: Journal of Geophysical Research - Oceans. - 0148-0227 .- 2156-2202. ; 118:1, s. 410-421
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Tidskriftsartikel (refereegranskat)abstract
- The upper halocline of the Arctic Ocean has a distinct chemical signature with high nutrient concentrations as well as low oxygen and pH values. This signature is formed in the Chukchi and East Siberian Seas, by a combination of mineralization of organic matter and release of decay products to the sea ice brine enriched bottom water. Salinity and total alkalinity data show that the fraction of sea ice brine in the nutrient enriched upper halocline water in the central Arctic Ocean is up to 4%. In the East Siberian Sea the bottom waters with exceptional high nutrient concentration and low pH have typically between 5 and 10% of sea ice brine as computed from salinity and oxygen-18 values. On the continental slope, over bottom depths of 15-200 m, the brine contribution was 6% at the nutrient maximum depth (50-100 m). At the same location as well as over the deeper basin the silicate maximum was found over a wider salinity range than traditionally found in the Canada Basin, in agreement with earlier observations east of the Chukchi Plateau. A detailed evaluation of the chemical and the temperature-salinity properties suggests at least two different areas for the formation of the nutrient rich halocline within the East Siberian Sea. This has not been observed before 2004 and it could be a sign of a changing marine climate in the East Siberian Sea, caused by more open water in the summer season followed by more sea ice formation and brine production in the fall/winter.
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| 9. |
- Anderson, Mattias, et al.
(författare)
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Total Synthesis of Capsaicin Analogues from Lignin-Derived Compounds by Combined Heterogeneous Metal, Organocatalytic and Enzymatic Cascades in One Pot
- 2014
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Ingår i: Advanced Synthesis and Catalysis. - : Wiley. - 1615-4150 .- 1615-4169. ; 356:9, s. 2113-2118
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Tidskriftsartikel (refereegranskat)abstract
- The total synthesis of capsaicin analogues was performed in one pot, starting from compounds that can be derived from lignin. Heterogeneous palladium nanoparticles were used to oxidise alcohols to aldehydes, which were further converted to amines by an enzyme cascade system, including an amine transaminase. It was shown that the palladium catalyst and the enzyme cascade system could be successfully combined in the same pot for conversion of alcohols to amines without any purification of intermediates. The intermediate vanillyl-amine, prepared with the enzyme cascade system, could be further converted to capsaicin analogues without any purification using either fatty acids and a lipase, or Schotten-Baumann conditions, in the same pot. An aldol compound (a simple lignin model) could also be used as starting material for the synthesis of capsaicin analogues. Using l-alanine as organocatalyst, vanillin could be obtained by a retro-aldol reaction. This could be combined with the enzyme cascade system to convert the aldol compound to vanillylamine in a one-step one-pot reaction.
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| 10. |
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| 11. |
- Dolberg Anderson, Ulrik, et al.
(författare)
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Fetal hemoglobin and alpha(1)-microglobulin as first- and early second-trimester predictive biomarkers for preeclampsia
- 2011
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Ingår i: American Journal of Obstetrics and Gynecology. - : Elsevier BV. - 1097-6868 .- 0002-9378. ; 204:6
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of this study was to evaluate fetal hemoglobin (HbF) and alpha(1)-microglobulin (A1M) in maternal serum as first-trimester biomarkers for preeclampsia (PE). STUDY DESIGN: The design was a case-control study. We included 96 patients in the first trimester of pregnancy (60 with PE and 36 controls). Venous serum samples were analyzed for HbF and total hemoglobin (Hb) by enzyme-linked immunosorbent assay and for A1M by radioimmunoassay. Sensitivity and specificity was calculated by logistic regression and receiver operating characteristic curve analysis. RESULTS: The HbF/Hb ratio and A1M concentration were significantly elevated in serum from women with subsequent development of PE (P < .0001). The optimal sensitivity and specificity was obtained using the biomarkers in combination; 69% sensitivity for a 5% screen positive rate and 90% sensitivity for a 23% screen positive rate. CONCLUSION: The study suggests that HbF/Hb ratio in combination with A1M is predictive biomarkers for PE.
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| 12. |
- Holmes, Michael V., et al.
(författare)
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Secretory Phospholipase A(2)-IIA and Cardiovascular Disease
- 2013
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 62:21, s. 1966-1976
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. less thanbrgreater than less thanbrgreater thanBackground Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA(2) inhibitor (varespladib) was stopped prematurely for lack of efficacy. less thanbrgreater than less thanbrgreater thanMethods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA(2)-IIA isoenzyme, as an instrumental variable. less thanbrgreater than less thanbrgreater thanResults PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA(2)-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. less thanbrgreater than less thanbrgreater thanConclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
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| 13. |
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| 14. |
- Larsson, P, et al.
(författare)
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Thiopentone elimination in newborn infants: exploring Michaelis-Menten kinetics.
- 2011
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 55, s. 444-451
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Tidskriftsartikel (refereegranskat)abstract
- Background: Thiopentone elimination has been described using Michaelis-Menten pharmacokinetics in adults after prolonged infusion or overdose, but there are few reports of elimination in neonates. Methods: Time-concentration profiles for neonates (n=37) given single-dose thiopentone were examined using both first-order (constant clearance) and mixed-order (Michaelis-Menten) elimination processes using nonlinear mixed effects models. These profiles included a 33-week post-menstrual age (PMA) neonate given an overdose. A two-compartment mamillary model was used to fit data. Parameter estimates were standardized to a 70 kg person using allometric models. Results: There were 197 observations available for analysis from neonates with a mean post-menstrual age of 35 (SD 4.5) weeks and a mean weight of 2.5 (SD 0.9) kg. They were given a mean thiopentone dose of 3 (SD 0.4) mg/kg as a rapid bolus. Clearance at 26 weeks PMA was 0.015 l/min/70 kg and increased to 0.119 l/min/70 kg by 42 weeks PMA. The maximum rate of elimination (V(max) ) at 26 weeks PMA was 0.22 mg/min/70 kg and increased to 4.13 mg/min/70 kg by 42 weeks PMA. These parameter estimates are approximately 40% adult values at term gestation. The Michaelis constant (K(m) ) was 28.3 [between subject variability (BSV) 46.4%, 95% confidence interval (CI) 4.49-99.2] mg/l; intercompartment clearance was 0.44 (BSV 97.5%, 95% CI 0.27-0.63) l/min/70 kg; central volume of distribution was 46.4 (BSV 29.2%, 95% CI 41.7-59.8) l/70 kg; peripheral volume of distribution was 95.7 (BSV 70.3%, 95% CI 61.3-128) l/70 kg. Conclusions: Both first-order and mixed-order processes satisfactorily described elimination. First-order elimination adequately described the time-concentration profile in the premature neonate given an overdose. Clearance is immature in the pre-term neonate although there is rapid maturation around 40 weeks PMA, irrespective of post-natal age.
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| 15. |
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| 16. |
- Peck, CC, et al.
(författare)
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Expanding the taxonomy of the diagnostic criteria for temporomandibular disorders
- 2014
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Ingår i: Journal of Oral Rehabilitation. - : John Wiley & Sons. - 1365-2842 .- 0305-182X. ; 41:1, s. 2-23
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Tidskriftsartikel (refereegranskat)abstract
- There is a need to expand the current temporomandibular disorders' (TMDs) classification to include less common but clinically important disorders. The immediate aim was to develop a consensus-based classification system and associated diagnostic criteria that have clinical and research utility for less common TMDs. The long-term aim was to establish a foundation, vis-à-vis this classification system, that will stimulate data collection, validity testing and further criteria refinement. A working group [members of the International RDC/TMD Consortium Network of the International Association for Dental Research (IADR), members of the Orofacial Pain Special Interest Group (SIG) of the International Association for the Study of Pain (IASP), and members from other professional societies] reviewed disorders for inclusion based on clinical significance, the availability of plausible diagnostic criteria and the ability to operationalise and study the criteria. The disorders were derived from the literature when possible and based on expert opinion as necessary. The expanded TMDs taxonomy was presented for feedback at international meetings. Of 56 disorders considered, 37 were included in the expanded taxonomy and were placed into the following four categories: temporomandibular joint disorders, masticatory muscle disorders, headache disorders and disorders affecting associated structures. Those excluded were extremely uncommon, lacking operationalised diagnostic criteria, not clearly related to TMDs, or not sufficiently distinct from disorders already included within the taxonomy. The expanded TMDs taxonomy offers an integrated approach to clinical diagnosis and provides a framework for further research to operationalise and test the proposed taxonomy and diagnostic criteria
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| 17. |
- Petterson, Gunilla, et al.
(författare)
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Climatic influence on the inter-annual variability of late-Holocene minerogenic sediment supply in a boreal forest catchment
- 2010
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Ingår i: Earth Surface Processes and Landforms. - : John Wiley & Sons. - 0197-9337 .- 1096-9837. ; 35:4, s. 390-398
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Tidskriftsartikel (refereegranskat)abstract
- Processes controlling sediment yield vary over a range of timescales, although most process-based observations are extremely short. Lake sediments, however, can be used to extend the observational timescale and are particularly useful when annually laminated (varved) sediment is present. The sediment record at Kassjön (N. Sweden) consists of ∼6400 varves, each 0·5–1 mm thick. Image analysis was used to determine grey-scale variation and varve thickness from which annual minerogenic accumulation rate (MinAR) (mg cm−2 year−1) was inferred for the period 4486 BC – AD 1900. MinAR varies on annual to centennial scales and mainly reflects channel bank erosion by the inflow streams. The mineral input reflects the intensity of the spring run-off, which is dependent on the amount of snow accumulated during the winter, and hence MinAR is a long-term record of variability in past winter climate; other factors will be a variable response to catchment uplift, vegetation succession and pedogenesis. A major shift from low to high MinAR occurred ∼250 BC, and peaks occurred around AD 250, 600, 1000, 1350 and 1650. Wavelet power spectrum analysis (confirmed by Fourier analyses) indicated significantly different periodicities throughout the period 4000 BC – AD 1700, including 275 years for the period 4000 BC – 2900 BC, 567 years for the period 2901 BC – 1201 BC, and 350 and 725 years for the period 1200 BC – AD 1700. The long-term, centennial scale variability (∼350 years) may reflect solar forcing (cf the 385-year peak in tree-ring calibrated 14C activity) but interestingly, there is no obvious link to high frequency forcing, such as the North Atlantic Oscillation. The high resolution component of the record highlights the relevance of varved lake sediment records for understanding erosion dynamics in undisturbed forested catchments and their link to long-term climate dynamics and future climate change.
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| 18. |
- Purrington, Kristen S., et al.
(författare)
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Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer
- 2014
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 35:5, s. 1012-1019
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Tidskriftsartikel (refereegranskat)abstract
- In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk relative to women with few variants.Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 x 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 x 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 x 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 x 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
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| 19. |
- Rosengren, Anna, et al.
(författare)
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The role of subsite +2 of the Trichoderma reesei beta-mannanase TrMan5A in hydrolysis and transglycosylation
- 2012
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Ingår i: Biocatalysis and Biotransformation. - : Informa UK Limited. - 1024-2422 .- 1029-2446. ; 30:3, s. 338-352
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Tidskriftsartikel (refereegranskat)abstract
- The N-terminal catalytic module of beta-mannanase TrMan5A from the filamentous fungus Trichoderma reesei is classified into family 5 of glycoside hydrolases. It is further classified in clan A with a (beta/alpha)(8) barrel configuration and has two catalytic glutamates (E169 and E276). It has at least five other residues conserved in family 5. Sequence alignment revealed that an arginine (R171 in TrMan5A) is semi-conserved among beta-mannanases in family 5. In a previously published mannobiose complex structure, this residue is positioned in hydrogen bonding distance from the C2 hydroxyl group of the mannose residue bound at the +2 subsite. To study the function of R171, mutants of this residue were constructed. The results show that arginine 171 is important for substrate binding and transglycosylation. A mutant of TrMan5A with the substitution R171K displayed retained activity on polymeric galactomannan but reduced activity on oligosaccharides due to an increase of K-m. While the wild-type enzyme produces mannobiose as dominant product from mannotetraose the R171K mutant shows an altered product profile, producing mannotriose and mannose. The cleavage pattern of mannotetraose was analysed with a method using isotope labelled water ((H2O)-O-18) and mass spectrometry which showed that the preferred productive binding mode of mannotetraose was shifted from subsite -2 to +2 in the wild-type to subsite -3 to +1 in the R171K mutant. Significant differences in product formation after manno-oligosaccharide incubation showed that the wild-type enzyme can perform transglycosylation on to saccharide acceptors while the R171K mutant cannot, likely due to loss of acceptor affinity. Interestingly, both enzymes show the ability to perform alcoholysis reactions with methanol and butanol, forming new beta-linked glyco-conjugates. Furthermore, it appears that the wild-type enzyme produces mainly mannobiose conjugates using M-4 as substrate, while in contrast the R171K mutant produces mainly mannotriose conjugates, due to the altered subsite binding.
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| 20. |
- Shore, N. D., et al.
(författare)
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New considerations for ADT in advanced prostate cancer and the emerging role of GnRH antagonists
- 2013
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Ingår i: Prostate Cancer and Prostatic Diseases. - : Springer Science and Business Media LLC. - 1476-5608 .- 1365-7852. ; 16:1, s. 7-15
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Forskningsöversikt (refereegranskat)abstract
- Androgen deprivation therapy (ADT) is first-line treatment for metastatic prostate cancer (PCa). Gonadotrophin-releasing hormone (GnRH) agonists are the most commonly used ADT but have several theoretical physiologic disadvantages (e.g. initial testosterone surge, potential microsurges upon repeat administration). Testosterone surge delays the intended serologic endpoint of testosterone suppression and may exacerbate clinical symptoms. GnRH antagonists were developed with a view toward overcoming these potential adverse physiologic events. This review evaluates GnRH agonists and antagonists, assessing the potential future role of antagonists in PCa and strategies to minimize ADT adverse events (AEs). Evidence was identified via PubMed search (by GnRH agent and other ADT-related terms), from review article bibliographies, and authors' therapy area knowledge, with articles included by author consensus. Degarelix shows similar efficacy to a GnRH agonist in achieving and maintaining castration, with faster onset and without testosterone surge/microsurges. Phase III data showed that, in the first treatment year, degarelix displayed a lower risk of PSA failure or death (composite endpoint), lower levels of the bone marker serum alkaline phosphatase (in baseline metastatic disease), and fewer musculoskeletal AEs than the agonist leuprolide. Also, crossing over from leuprolide to degarelix after 1 year reduced the risk of PSA failure or death. ADT displays an AE spectrum which can impact quality of life as well as causing significant morbidities. Strategies to improve ADT tolerability have become increasingly important including: a holistic management approach, improved diet and exercise, more specific monitoring to detect and prevent testosterone depletion toxicities, and intermittent ADT allowing hormonal recovery between treatment periods. Clinical studies suggest possible benefits of GnRH antagonists over agonists based on different mechanisms of action. GnRH antagonists should now be considered as an alternative first-line ADT option in advanced PCa. Intermittent ADT and a holistic treatment approach are promising strategies to improve ADT tolerability. Prostate Cancer and Prostatic Diseases (2013) 16, 7-15; doi:10.1038/pcan.2012.25; published online 3 July 2012
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| 21. |
- Smith, Margaretha E., et al.
(författare)
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Increase in Net Activity of Serine Proteinases but Not Gelatinases after Local Endotoxin Exposure in the Peripheral Airways of Healthy Subjects
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9
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Tidskriftsartikel (refereegranskat)abstract
- We tested the hypothesis that activation of the innate immune response induces an imbalance in the proteolytic homeostasis in the peripheral airways of healthy subjects, towards excess serine or gelatinase proteinase activity. During bronchoscopy, 18 healthy human subjects underwent intra-bronchial exposure to endotoxin and contra-lateral exposure to vehicle. Bronchoalveolar lavage (BAL) samples were harvested 24 or 48 hours (h) later. We quantified archetype proteinases, anti-proteinases, inflammatory BAL cells, and, importantly, total plus net proteinase activities using functional substrate assays. As expected, endotoxin exposure increased the concentrations of polymorphonuclear leukocytes (PMN's) and macrophages, of proteinases and the anti-proteinases tissue inhibitor of metalloproteinase-1, alpha-1-antitrypsin and, to a lesser extent, secretory leukoproteinase inhibitor, at both time points. Notably, at these time points, endotoxin exposure substantially increased the quantitative NE/SLPI ratio and the net serine proteinase activity corresponding to neutrophil elastase (NE). Endotoxin exposure also increased the total gelatinase activity corresponding to matrix metalloproteinase (MMP)-9; an activity dominating over that of MMP-2. However, endotoxin exposure had no impact on net gelatinolytic activity at 24 or 48 h after exposure. Thus, local activation of the innate immune response induces an imbalance towards increased net serine proteinase activity in the proteolytic homeostasis of the peripheral airways in healthy subjects. Hypothetically, this serine proteinase activity can contribute to tissue remodelling and hypersecretion via NE from PMN's, if it is triggered repeatedly, as might be the case in chronic inflammatory airway disorders.
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| 22. |
- Stenström, Martin, et al.
(författare)
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Selective depletion of splenic CD4 dendritic cells in mice treated with immunomodulatory quinoline-3-carboxamide ABR-215757.
- 2010
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Ingår i: International Immunopharmacology. - : Elsevier BV. - 1878-1705 .- 1567-5769. ; May 4, s. 837-842
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Tidskriftsartikel (refereegranskat)abstract
- The quinoline-3-carboxamide ABR-215757 (5757) is in clinical development for the treatment of human SLE and has shown efficacy in several mouse models of T cell-mediated inflammatory autoimmune disease. The goal of this study was to determine the impact of 5757 on steady state immune cells. We show that the number of splenic CD4 dendritic cells (DCs) was reduced in 5757-treated mice, while there was no effect on other splenic DC populations, on DCs in lymph nodes or on lymphocytes. This reduction was fully reversible and the kinetics of CD4 DC loss during exposure and recovery after withdrawal of treatment were identical. The loss of CD4 DCs was neither caused by reduced proliferation nor by increased apoptosis. CD4 DCs reside in the splenic marginal zone, but the loss of these cells did not influence other cell populations at this site. The similar kinetics of the decay and repopulation of the splenic CD4 DC compartment suggests that the reduced number of CD4 DC in 5757 treated mice may be a result of blockade of CD4 DC precursor development in the spleen and not of toxicity. Alternatively, induced emigration of CD4 DC to the periphery, or an interference with adherence of these cells in the spleen marginal zone, may also explain our data.
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| 23. |
- Sundbom, Per, et al.
(författare)
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The place of skin cancer screening in heart transplant recipient follow-up protocols: a case series
- 2014
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Ingår i: Enliven: Surgery and Transplantation. - : Enliven Archive. - 2379-5719. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesFor solid organ transplant recipients the risk of skin cancer is markedly increased due to immunosuppression. Many studies propose an annual, or morefrequent, skin screening program by a dermatologist. As the number of transplant recipients increases and survival times improve, the need for screeningand rapid response (as required) access is increasing.DesignIn a quality control study we retrospectively examined the medical records of patients participating in an annual screening program between 1997 and2012. A total of 69 medical records were studied and we here describe the program and present the findings.ResultsWe found malignant melanoma in 3 cases. Cutaneous squamous cell carcinoma occurred in 16 patients and basal cell carcinoma in 12 patients. Themost frequent skin lesions were actinic keratoses, reported in 20 patients.ConclusionsIncidence rates for all diagnoses were elevated compared to the general population. Awareness of the increased risk for skin malignancies is of importanceto those involved in the care of solid organ transplant recipients. Routines for early discovery of skin tumors are needed both in the form of screening,which can also establish risk group status and give preventive education, and as rapid response access for skin lesion diagnosis and treatment.
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| 24. |
- Wärnberg, Fredrik, et al.
(författare)
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Effect of Radiotherapy After Breast-Conserving Surgery for Ductal Carcinoma in Situ: 20 Years Follow-Up in the Randomized SweDCIS Trial
- 2014
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 32:32, s. 3613-
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Four randomized studies show that adjuvant radiotherapy (RT) lowers the risk of subsequent ipsilateral breast events (IBEs) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) by approximately 50% after 10 to 15 years. We present 20 years of follow-up data for the SweDCIS trial. Patients and Methods Between 1987 and 1999 1,046 women were randomly assigned to RT or not after BCS for primary DCIS. Results up to 2005 have been published, and we now add another 7 years of follow-up. All breast cancer events and causes of death were registered. Results There were 129 in situ and 129 invasive IBEs. Absolute risk reduction in the RT arm was 12.0% at 20 years (95% CI, 6.5 to 17.7), with a relative risk reduction of 37.5%. Absolute reduction was 10.0% (95% CI, 6.0 to 14.0) for in situ and 2.0% (95% CI, -3.0 to 7.0) for invasive IBEs. There was a nonstatistically significantly increased number of contralateral events in the RT arm (67 v 48 events; hazard ratio, 1.38; 95% CI, 0.95 to 2.00). Breast cancer-specific death and overall survival were not influenced. Younger women experienced a relatively higher risk of invasive IBE and lower effect of RT. The hazard over time looked different for in situ and invasive IBEs. Conclusion Use of adjuvant RT is supported by 20-year follow-up. Modest protection against invasive recurrences and a possible increase in contralateral cancers still call for a need to find groups of patients for whom RT could be avoided or mastectomy with breast reconstruction is indicated.
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| 25. |
- Ziker, John, et al.
(författare)
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Indigenous peoples and demography
- 2010
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Ingår i: Anthropology News. - : American Anthropological Association. - 1541-6151 .- 1556-3502. ; 51:5, s. 10-12
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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