| 31. |
- Boukharta, Lars, et al.
(författare)
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Computer Simulations of Structure-Activity Relationships for hERG Channel Blockers
- 2011
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 50:27, s. 6146-6156
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Tidskriftsartikel (refereegranskat)abstract
- The hERG potassium channel is of major pharmaceutical importance, and its blockade by various compounds, potentially causing serious cardiac side effects, is a major problem in drug development. Despite the large amounts of existing biochemical data on blockade of hERG by drugs and druglike compounds, relatively little is known regarding the structural basis of binding of blockers to the channel. Here, we have used a recently developed homology model of hERG to conduct molecular docking experiments with a series of channel blockers, followed by molecular dynamics simulations of the complexes and evaluation of binding free energies with the linear interaction energy method. The calculations yield a remarkably good agreement with experimental binding affinities and allow for a rationalization of three-dimensional structure-activity relationships in terms of a number of key interactions. Two main interaction regions of the channel are thus identified with implications for further mutagenesis experiments and design of new compounds.
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| 32. |
- Calissendorff, Jan, et al.
(författare)
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Long-Term Outcome of Graves' Disease : A Gender Perspective
- 2023
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Ingår i: Women's Health Reports. - : Mary Ann Liebert. - 2688-4844. ; 4:1, s. 487-496
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: In gender-skewed conditions such as Graves' disease (GD), the outcome naturally becomes dominated by the majority. This may lead to gender-biased misunderstandings regarding treatment outcomes. This especially holds true when complications, such as depression, are unevenly distributed. We have, therefore, studied the long-term outcome of GD from a gender perspective.Materials and Methods: A cohort of 1186 patients with GD was included in a follow-up 6-10 years after inclusion. Choice of treatment, the feeling of recovery, long-term treatment, comorbidity, and quality of life were investigated with questionnaires. All results were studied sex-divided.Results: We included 973 women and 213 men. There was no difference between men and women in the choice of treatment. At follow-up, women scored significantly worse in the general questionnaire 36-item Short-Form Health Status (SF-36) domain bodily pain and in the thyroid-specific Thyroid-Related Patient-Reported Outcome (ThyPRO) domains depression, impaired sex life, and cosmetic complaints, all p < 0.05. Women were twice as likely (29.5%) to be treated with levothyroxine after successful treatment with antithyroid drugs (ATD) compared with men (14.9%, p < 0.05).Conclusion: After treatment for GD, women were more affected by depression, impaired sex life, cosmetic issues, and bodily pain despite successful cure of hyperthyroidism. The prevalence of hypothyroidism was also doubled in women. Whether these observed gender differences reflect a worse outcome of GD in women or a natural consequence of a higher prevalence of these symptoms and autoimmunity in the female population is difficult to disentangle. Nevertheless, several years after GD, women reveal more persistent symptoms.
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| 33. |
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| 34. |
- Crouse, Kristine, et al.
(författare)
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Acclimation of light and dark respiration to experimental and seasonal warming are mediated by changes in leaf nitrogen in Eucalyptus globulus
- 2017
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Ingår i: Tree Physiology. - : Oxford University Press (OUP). - 0829-318X .- 1758-4469. ; 37:8, s. 1069-1083
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Tidskriftsartikel (refereegranskat)abstract
- Quantifying the adjustments of leaf respiration in response to seasonal temperature variation and climate warming is crucial because carbon loss from vegetation is a large but uncertain part of the global carbon cycle. We grew fast-growing Eucalyptus globulus Labill. trees exposed to +3 °C warming and elevated CO2 in 10-m tall whole-tree chambers and measured the temperature responses of leaf mitochondrial respiration, both in light (RLight) and in darkness (RDark), over a 20–40 °C temperature range and during two different seasons. RLight was assessed using the Laisk method. Respiration rates measured at a standard temperature (25 °C – R25) were higher in warm-grown trees and in the warm season, related to higher total leaf nitrogen (N) investment with higher temperatures (both experimental and seasonal), indicating that leaf N concentrations modulated the respiratory capacity to changes in temperature. Once differences in leaf N were accounted for, there were no differences in R25 but the Q10 (i.e., short-term temperature sensitivity) was higher in late summer compared with early spring. The variation in RLight between experimental treatments and seasons was positively correlated with carboxylation capacity and photorespiration. RLight was less responsive to short-term changes in temperature than RDark, as shown by a lower Q10 in RLight compared with RDark. The overall light inhibition of R was ∼40%. Our results highlight the dynamic nature of leaf respiration to temperature variation and that the responses of RLight do not simply mirror those of RDark. Therefore, it is important not to assume that RLight is the same as RDark in ecosystem models, as doing so may lead to large errors in predicting plant CO2 release and productivity.
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| 35. |
- Cuni-Sanchez, Aida, et al.
(författare)
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High aboveground carbon stock of African tropical montane forests
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 596:7873, s. 536-542
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Tidskriftsartikel (refereegranskat)abstract
- Tropical forests store 40–50per cent of terrestrial vegetation carbon. However, spatial variations in aboveground live tree biomass carbon (AGC) stocks remain poorly understood, in particular in tropical montane forests. Owing to climatic and soil changes with increasing elevation, AGC stocks are lower in tropical montane forests compared with lowland forests. Here we assemble and analyse a dataset of structurally intact old-growth forests (AfriMont) spanning 44 montane sites in 12 African countries. We find that montane sites in the AfriMont plot network have a mean AGC stock of 149.4megagrams of carbon per hectare (95% confidence interval 137.1–164.2), which is comparable to lowland forests in the African Tropical Rainforest Observation Network4 and about 70per cent and 32per cent higher than averages from plot networks in montane and lowland forests in the Neotropics, respectively. Notably, our results are two-thirds higher than the Intergovernmental Panel on Climate Change default values for these forests in Africa8. We find that the low stem density and high abundance of large trees of African lowland forests is mirrored in the montane forests sampled. This carbon store is endangered: we estimate that 0.8 million hectares of old-growth African montane forest have been lost since 2000. We provide country-specific montane forest AGC stock estimates modelled from our plot network to helpto guide forest conservation and reforestation interventions. Our findings highlight the need for conserving these biodiverse and carbon-rich ecosystems.
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| 36. |
- Dahle, B., et al.
(författare)
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Predation on adult moose Alces alces by European brown bears Ursus arctos
- 2013
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Ingår i: Wildlife Biology. - : Wiley. - 0909-6396 .- 1903-220X. ; 19:2, s. 165-169
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Tidskriftsartikel (refereegranskat)abstract
- Several North American studies have reported significant predation rates on moose Alces alces by brown bears Ursus arctos. We documented predation on moose by brown bears in south-central Sweden, where brown bears and moose occurred at estimated densities of 10-30 and 400-1,340/1,000 km(2), respectively. Bears killed 0.8% of radio-collared adult female moose (i.e. >= 1 year old) annually and no male moose (>= 1 year old). Bear predation was the least important mortality factor we documented. Based on tracking brown bears on snow during spring we recorded one successful hunt for every 372 km of tracks and documented attacks only by adult bears and successful attacks only by adult males. Autopsy of moose older than calves that were killed by brown bears revealed that yearlings were more prone to predation than older moose, and that older (i.e. >= 2 years) cows were more vulnerable to predation than older bulls. Our study suggests a lower tendency for Scandinavian brown bears to prey on moose compared to most of the North American studies.
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| 37. |
- Dammeyer, Pascal, et al.
(författare)
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Cisplatin and oxaliplatin are toxic to cochlear outer hair cells and both target thioredoxin reductase in organ of Corti cultures
- 2014
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 134:5, s. 448-454
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Tidskriftsartikel (refereegranskat)abstract
- Conclusion: Inhibition of thioredoxin reductase (TrxR) may be a contributing factor in cisplatin- induced ototoxicity. Direct exposure of organ of Corti to cisplatin and oxaliplatin gives equal loss of hair cells. Objectives: Platinum- containing drugs are known to target the anti- oxidant selenoprotein TrxR in cancer cells. Two such anti- cancer, platinum- containing drugs, cisplatin and oxaliplatin, have different side effects. Only cisplatin induces hearing loss, i.e. has an ototoxic side effect that is not seen after treatment with oxaliplatin. The objective of this study was to evaluate if TrxR is a target in the cochlea. Loss of outer hair cells was also compared when cisplatin and oxaliplatin were administered directly to the organ of Corti. Methods: Organ of Corti cell culture was used for direct exposure to cisplatin and oxaliplatin. Hair cells were evaluated and the level of TrxR was assessed. Immunohistochemical staining for TrxR was performed. An animal model was used to evaluate the effect on TrxR after treatment with cisplatin and oxaliplatin in vivo. Results: Direct exposure of cochlear organotypic cultures to either cisplatin or oxaliplatin induced comparable levels of outer hair cell loss and inhibition of TrxR, demonstrating that both drugs are similarly ototoxic provided that the cochlea becomes directly exposed.
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| 38. |
- Daskalakis, Kosmas, 1979-, et al.
(författare)
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Modified Histopathological Grading Optimizes Prediction of Survival Outcomes in Small Intestinal Neuroendocrine Tumours
- 2024
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197.
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: One of the major prognostic indices in neuroendocrine tumours (NETs) is Ki67 proliferation index.OBJECTIVE: To identify optimal grading Ki-67 cut-offs to delineate differences in prognosis of patients with small intestinal NETs (SI-NETs).DESIGN, SETTING, PARTICIPANTS: Multicentre retrospective cohort analysis of 551 SI-NET patients diagnosed from 1993 through 2021 at five European referral centres with a mean(±SD) follow-up time of 51.5(±52.9) months.MAIN OUTCOME MEASURES: Overall- and event-free survival (OS and EFS) rates.RESULTS: Median age at baseline was 62.3(range:17-90) years; 252(45.7%) patients were female. All SI-NETs were well-differentiated with 326 being grade 1(G1; 59.2%), 169G2(30.7%), and only 8G3(1.5), while 48 tumours were of unspecified grade (8.7%). The median Ki67 was 2%(range:1-70%). Two-hundred forty-seven patients (44.8%) had distant metastases at baseline (stage IV), 217 locoregional disease (41.1%; stage III), whereas 29(7.1%) and 25(4.5%) presented at stages II and I, respectively. The median OS was 214.7(95%CI:152.7-276.6) months and the median EFS was 79.8(95%CI:68.2-91.5) months, respectively. In multivariable Cox-regression OS analysis, the proposed modified histopathological Ki67 grading system (K67:5-10% group: HR=2.2, 95%CI:1.15-4.31; p=0.018 and K67≥10% group: HR=5.11, 95%CI:2.87-9.09; p<0.001), age (HR=1.07, 95%CI:1.04-1.09; p<0.001), Charlson Comorbidity Index (HR=1.08, 95%CI:1-1.16; p=0.028) and TNM stage (HR=1.79, 95%CI:1.05-3.06; p=0.034) were independent predictors for death. Pertinent EFS analysis, confirmed the proposed modified histopathological Ki67 grading system (K67≥10% group: HR=4.01, 95%CI:2.6-6.37; p<0.001) and age (HR=1.04, 95%CI:1.02-1.05; p<0.001) as independent predictors for recurrence, progression and/or death.CONCLUSIONS: Ki-67 proliferation index was a strong and independent predictor of OS and EFS. A modified histopathological grading system applying Ki-67 cut-offs of 5 and 10% could be superior to predict differences in SI-NET patient survival outcomes.
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| 39. |
- Daskalakis, Kosmas, 1979-, et al.
(författare)
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MODIFIED HISTOPATHOLOGICAL GRADING OPTIMIZES PREDICTION OF SURVIVAL OUTCOMES IN SMALL INTESTINAL NEUROENDOCRINE TUMOURS
- 2024
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Ingår i: British Journal of Surgery. - : Oxford University Press. - 0007-1323 .- 1365-2168. ; 111:Suppl. 4
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: We aimed to identify optimal grading Ki-67 cut-offs to delineate differences in prognosis of patients with small intestinal neuroendocrine tumours (SI-NETs) in terms of overall- and event-free survival rates.Methods: We included 551 patients with SI-NETs diagnosed from June 15th, 1993, through March 8th, 2021, identified using the SI-NET databases from five European referral centers.Results: Median age at baseline was 62.3(17-90) years; 252 patients were women (45.7%). All tumours were well-differentiated; 326 were G1 tumours (59.2%), 169 G2(30.7%), only 8 G3(1.5%), while 48 tumourswere of unspecified grade (8.7%). The median Ki67 was 2%(1-70%). 247 patients(44.8%) had distant metastases at baseline (stage IV), 217locoregional disease (41.1%; stage III), whereas 29(7.1%) and 25(4.5%) presented at stages II and I, respectively. Within a mean(SD) follow-up of 51.5(52.9) months, 94 patients(17.1%) died, whereas overall 188 experienced disease recurrence, progression and/or death(34.1%). The median OS was 214.7(95%CI: 152.7-276.6) months and the median EFS was 79.8(95%CI: 68.2-91.5) months, respectively. In multivariable Cox-regression OS analysis, age (HR=1.07, 95%CI: 1.04-1.09; p<0.001), Charlson Comorbidity Index(HR=1.1, 95%CI: 1.03-1.17; p=0.006) and the proposed modified histopathological Ki67 grading system(K67:5-10% group: HR=2.4, 95%CI: 1.3-4.5; p=0.007 and K67≥10% group: HR=5.1, 95%CI: 2.9-9.2; p<0.001) were independent predictors for death. Pertinent EFS analysis, confirmed age(HR=1.04, 95%CI: 1.02-1.05;p<0.001) and the proposed modified histopathological Ki67 grading system(K67≥10% group: HR=4; 95%CI:2.5-6.2;p<0.001) as independent predictors for recurrence, progression and/or death.Conclusions: Ki-67 proliferation index is an independent predictor of EFS and OS. A modified site-specific histopathological grading system applying Ki-67 cut-offs of 5% and 10% seems more optimal to predict differences in SI-NET patient prognosis
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| 40. |
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