| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Wang, Zhaoming, et al.
(author)
-
Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
-
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
-
Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
|
|
| 6. |
- Sampson, Joshua N., et al.
(author)
-
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
-
In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
-
Journal article (peer-reviewed)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
|
|
| 7. |
- Ademuyiwa, Adesoji O., et al.
(author)
-
Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
-
In: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
-
Journal article (peer-reviewed)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
|
|
| 8. |
|
|
| 9. |
- Kalman, L. V., et al.
(author)
-
Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting
- 2016
-
In: Clinical Pharmacology and Therapeutics. - : WILEY-BLACKWELL. - 0009-9236 .- 1532-6535. ; 99:2, s. 172-185
-
Journal article (peer-reviewed)abstract
- This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.
|
|
| 10. |
- Antonelli, Alexandre, 1978, et al.
(author)
-
Madagascar's extraordinary biodiversity : Evolution, distribution, and use
- 2022
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 378:6623, s. 962-
-
Journal article (peer-reviewed)abstract
- Madagascar's biota is hyperdiverse and includes exceptional levels of endemicity. We review the current state of knowledge on Madagascar's past and current terrestrial and freshwater biodiversity by compiling and presenting comprehensive data on species diversity, endemism, and rates of species description and human uses, in addition to presenting an updated and simplified map of vegetation types. We report a substantial increase of records and species new to science in recent years; however, the diversity and evolution of many groups remain practically unknown (e.g., fungi and most invertebrates). Digitization efforts are increasing the resolution of species richness patterns and we highlight the crucial role of field- and collections-based research for advancing biodiversity knowledge and identifying gaps in our understanding, particularly as species richness corresponds closely to collection effort. Phylogenetic diversity patterns mirror that of species richness and endemism in most of the analyzed groups. We highlight humid forests as centers of diversity and endemism because of their role as refugia and centers of recent and rapid radiations. However, the distinct endemism of other areas, such as the grassland-woodland mosaic of the Central Highlands and the spiny forest of the southwest, is also biologically important despite lower species richness. The documented uses of Malagasy biodiversity are manifold, with much potential for the uncovering of new useful traits for food, medicine, and climate mitigation. The data presented here showcase Madagascar as a unique " living laboratory" for our understanding of evolution and the complex interactions between people and nature. The gathering and analysis of biodiversity data must continue and accelerate if we are to fully understand and safeguard this unique subset of Earth's biodiversity.
|
|
| 11. |
- de Winter, J M, et al.
(author)
-
KBTBD13 is an actin-binding protein that modulates muscle kinetics
- 2020
-
In: Journal of Clinical Investigation. - : Stanford University Press. - 0021-9738 .- 1558-8238. ; 130:2, s. 754-767
-
Journal article (peer-reviewed)abstract
- The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13(R408c)-knockin mouse models, and a GFP-labeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin - a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.
|
|
| 12. |
- Grote, V. A., et al.
(author)
-
Diabetes mellitus, glycated haemoglobin and C-peptide levels in relation to pancreatic cancer risk : a study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
- 2011
-
In: Diabetologia. - New York : Springer-Verlag New York. - 0012-186X .- 1432-0428. ; 54:12, s. 3037-3046
-
Journal article (peer-reviewed)abstract
- Aims/hypothesis: There has been long-standing debate about whether diabetes is a causal risk factor for pancreatic cancer or a consequence of tumour development. Prospective epidemiological studies have shown variable relationships between pancreatic cancer risk and blood markers of glucose and insulin metabolism, overall and as a function of lag times between marker measurements (blood donation) and date of tumour diagnosis.Methods: Pre-diagnostic levels of HbA(1c) and C-peptide were measured for 466 participants with pancreatic cancer and 466 individually matched controls within the European Prospective Investigation into Cancer and Nutrition. Conditional logistic regression models were used to estimate ORs for pancreatic cancer.Results: Pancreatic cancer risk gradually increased with increasing pre-diagnostic HbA(1c) levels up to an OR of 2.42 (95% CI 1.33, 4.39 highest [>= 6.5%, 48 mmol/mol] vs lowest [<= 5.4%, 36 mmol/mol] category), even for individuals with HbA(1c) levels within the non-diabetic range. C-peptide levels showed no significant relationship with pancreatic cancer risk, irrespective of fasting status. Analyses showed no clear trends towards increasing hyperglycaemia (as marked by HbA(1c) levels) or reduced pancreatic beta cell responsiveness (as marked by C-peptide levels) with decreasing time intervals from blood donation to cancer diagnosis.Conclusions/interpretation: Our data on HbA(1c) show that individuals who develop exocrine pancreatic cancer tend to have moderate increases in HbA(1c) levels, relatively independently of obesity and insulin resistance-the classic and major risk factors for type 2 diabetes. While there is no strong difference by lag time, more data are needed on this in order to reach a firm conclusion.
|
|
| 13. |
- Grote, V. A., et al.
(author)
-
Inflammation marker and risk of pancreatic cancer: A nested case-control study within the EPIC cohort
- 2012
-
In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 106, s. 1866-1874
-
Journal article (peer-reviewed)abstract
- Background: Established risk factors for pancreatic cancer include smoking, long-standing diabetes, high body fatness, and chronic pancreatitis, all of which can be characterised by aspects of inflammatory processes. However, prospective studies investigating the relation between inflammatory markers and pancreatic cancer risk are scarce. Methods: We conducted a nested case-control study within the European Prospective Investigation into Cancer and Nutrition, measuring prediagnostic blood levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble receptors of tumour necrosis factor-α (sTNF-R1, R2) in 455 pancreatic cancer cases and 455 matched controls. Odds ratios (ORs) were estimated using conditional logistic regression models. Results: None of the inflammatory markers were significantly associated with risk of pancreatic cancer overall, although a borderline significant association was observed for higher circulating sTNF-R2 (crude OR=1.52 (95% confidence interval (CI) 0.97-2.39), highest vs lowest quartile). In women, however, higher sTNF-R1 levels were significantly associated with risk of pancreatic cancer (crude OR=1.97 (95% CI 1.02-3.79)). For sTNF-R2, risk associations seemed to be stronger for diabetic individuals and those with a higher BMI. Conclusion: Prospectively, CRP and IL-6 do not seem to have a role in our study with respect to risk of pancreatic cancer, whereas sTNF-R1 seemed to be a risk factor in women and sTNF-R2 might be a mediator in the risk relationship between overweight and diabetes with pancreatic cancer. Further large prospective studies are needed to clarify the role of proinflammatory proteins and cytokines in the pathogenesis of exocrine pancreatic cancer. © 2012 Cancer Research UK.
|
|
| 14. |
- Rohrmann, S., et al.
(author)
-
Concentrations of IGF-I and IGFBP-3 and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition
- 2012
-
In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 106, s. 1004-1010
-
Journal article (peer-reviewed)abstract
- Background: Insulin-like growth factors (IGFs) and their binding proteins (BPs) regulate cell differentiation, proliferation and apoptosis, and may have a role in the aetiology of various cancers. Information on their role in pancreatic cancer is limited and was examined here in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition.Methods:Serum concentrations of IGF-I and IGFBP-3 were measured using enzyme-linked immunosorbent assays in 422 cases and 422 controls matched on age, sex, study centre, recruitment date, and time since last meal. Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) adjusted for confounding variables.Results:Neither circulating levels of IGF-I (OR=1.21, 95% CI 0.75-1.93 for top vs bottom quartile, P-trend 0.301), IGFBP-3 (O=R1.00, 95% CI 0.66-1.51, P-trend 0.79), nor the molar IGF-I/IGFBP-3 ratio, an indicator of free IGF-I level (OR=1.22, 95% CI 0.75-1.97, P-trend 0.27), were statistically significantly associated with the risk of pancreatic cancer. In a cross-classification, however, a high concentration of IGF-I with concurrently low levels of IGFBP-3 was related to an increased risk of pancreatic cancer (OR=1.72, 95% CI 1.05-2.83; P-interaction0.154). Conclusion: On the basis of these results, circulating levels of components of the IGF axis do not appear to be the risk factors for pancreatic cancer. However, on the basis of the results of a subanalysis, it cannot be excluded that a relatively large amount of IGF-1 together with very low levels of IGFBP-3 might still be associated with an increase in pancreatic cancer risk. © 2012 Cancer Research UK All rights reserved.
|
|
| 15. |
|
|
| 16. |
- Abele, H., et al.
(author)
-
Particle physics at the European Spallation Source
- 2023
-
In: Physics reports. - : Elsevier. - 0370-1573 .- 1873-6270. ; 1023, s. 1-84
-
Research review (peer-reviewed)abstract
- Presently under construction in Lund, Sweden, the European Spallation Source (ESS) will be the world’s brightest neutron source. As such, it has the potential for a particle physics program with a unique reach and which is complementary to that available at other facilities. This paper describes proposed particle physics activities for the ESS. These encompass the exploitation of both the neutrons and neutrinos produced at the ESS for high precision (sensitivity) measurements (searches).
|
|
| 17. |
- Caravaca, A. S., et al.
(author)
-
Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit
- 2022
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:22
-
Journal article (peer-reviewed)abstract
- Nonresolving inflammation underlies a range of chronic inflammatory diseases, and therapeutic acceleration of resolution of inflammation may improve outcomes. Neural reflexes regulate the intensity of inflammation (for example, through signals in the vagus nerve), but whether activation of the vagus nerve promotes the resolution of inflammation in vivo has been unknown. To investigate this, mice were subjected to electrical vagus nerve stimulation (VNS) or sham surgery at the cervical level followed by zymosan-induced peritonitis. The duration of inflammation resolution was significantly reduced and efferocytosis was significantly increased in mice treated with VNS as compared with sham. Lipid mediator (LM) metabololipidomics revealed that mice treated with VNS had higher levels of specialized proresolving mediators (SPMs), particularly from the omega-3 docosahexaenoic (DHA) and docosapentaenoic (n-3 DPA) metabolomes, in peritoneal exudates. VNS also shifted the ratio between proinflammatory and proresolving LMs toward a proresolving profile, but this effect by VNS was inverted in mice deficient in 12/15-lipoxgenase (Alox15), a key enzyme in this SPM biosynthesis. The significant VNS-mediated reduction of neutrophil numbers in peritoneal exudates was absent in mice deficient in the cholinergic α7-nicotinic acetylcholine receptor subunit (α7nAChR), an essential component of the inflammatory reflex. Thus, VNS increased local levels of SPM and accelerated resolution of inflammation in zymosan-induced peritonitis by a mechanism that involves Alox15 and requires the α7nAChR.
|
|
| 18. |
- Farley, K.A., et al.
(author)
-
In situ radiometric and exposure age dating of the martian surface
- 2014
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 343:6169
-
Journal article (peer-reviewed)abstract
- We determined radiogenic and cosmogenic noble gases in a mudstone on the floor of Gale Crater. A K-Ar age of 4.21 ± 0.35 billion years represents a mixture of detrital and authigenic components and confirms the expected antiquity of rocks comprising the crater rim. Cosmic-ray-produced 3He, 21Ne, and 36Ar yield concordant surface exposure ages of 78 ± 30 million years. Surface exposure occurred mainly in the present geomorphic setting rather than during primary erosion and transport. Our observations are consistent with mudstone deposition shortly after the Gale impact or possibly in a later event of rapid erosion and deposition. The mudstone remained buried until recent exposure by wind-driven scarp retreat. Sedimentary rocks exposed by this mechanism may thus offer the best potential for organic biomarker preservation against destruction by cosmic radiation.
|
|
| 19. |
- Fedirko, V., et al.
(author)
-
Glycemic index, glycemic load, dietary carbohydrate, and dietary fiber intake and risk of liver and biliary tract cancers in Western Europeans
- 2013
-
In: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 24:2, s. 543-553
-
Journal article (peer-reviewed)abstract
- Background: The type and quantity of dietary carbohydrate as quantified by glycemic index (GI) and glycemic load (GL), and dietary fiber may influence the risk of liver and biliary tract cancers, but convincing evidence is lacking. Patients and methods: The association between dietary GI/GL and carbohydrate intake with hepatocellular carcinoma (HCC; N = 191), intrahepatic bile duct (IBD; N = 66), and biliary tract (N = 236) cancer risk was investigated in 477 206 participants of the European Prospective Investigation into Cancer and Nutrition cohort. Dietary intake was assessed by country-specific, validated dietary questionnaires. Hazard ratios and 95% confidence intervals were estimated from proportional hazard models. HBV/HCV status was measured in a nested case-control subset. Results: Higher dietary GI, GL, or increased intake of total carbohydrate was not associated with liver or biliary tract cancer risk. For HCC, divergent risk estimates were observed for total sugar = 1.43 (1.17-1.74) per 50 g/day, total starch = 0.70 (0.55-0.90) per 50 g/day, and total dietary fiber = 0.70 (0.52-0.93) per 10 g/day. The findings for dietary fiber were confirmed among HBV/HCV-free participants [0.48 (0.23-1.01)]. Similar associations were observed for IBD [dietary fiber = 0.59 (0.37-0.99) per 10 g/day], but not biliary tract cancer. Conclusions: Findings suggest that higher consumption of dietary fiber and lower consumption of total sugars are associated with lower HCC risk. In addition, high dietary fiber intake could be associated with lower IBD cancer risk. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
|
|
| 20. |
- Gau, Rémi, et al.
(author)
-
Brainhack : Developing a culture of open, inclusive, community-driven neuroscience
- 2021
-
In: Neuron. - : Elsevier. - 0896-6273 .- 1097-4199. ; 109:11, s. 1769-1775
-
Journal article (peer-reviewed)abstract
- Brainhack is an innovative meeting format that promotes scientific collaboration and education in an open, inclusive environment. This NeuroView describes the myriad benefits for participants and the research community and how Brainhacks complement conventional formats to augment scientific progress.
|
|
| 21. |
- Imai, Y., et al.
(author)
-
Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury
- 2008
-
In: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 133:2, s. 235-249
-
Journal article (peer-reviewed)abstract
- Multiple lung pathogens such as chemical agents, H5N1 avian flu, or SARS cause high lethality due to acute respiratory distress syndrome. Here we report that Toll-like receptor 4 (TLR4) mutant mice display natural resistance to acid-induced acute lung injury (ALI). We show that TLR4-TRIF-TRAF6 signaling is a key disease pathway that controls the severity of ALI. The oxidized phospholipid (OxPL) OxPAPC was identified to induce lung injury and cytokine production by lung macrophages via TLR4-TRIF. We observed OxPL production in the lungs of humans and animals infected with SARS, Anthrax, or H5N1. Pulmonary challenge with an inactivated H5N1 avian influenza virus rapidly induces ALI and OxPL formation in mice. Loss of TLR4 or TRIF expression protects mice from H5N1-induced ALI. Moreover, deletion of ncf1, which controls ROS production, improves the severity of H5N1-mediated ALI. Our data identify oxidative stress and innate immunity as key lung injury pathways that control the severity of ALI.
|
|
| 22. |
- Sandeman, S., et al.
(author)
-
Characterising Nanoporous Carbon Adsorbents for Biological Application to Chronic Kidney Disease
- 2012
-
In: Journal of Biomaterials and Tissue Engineering. - : American Scientific Publishers. - 2157-9083 .- 2157-9091. ; 2:1, s. 40-47
-
Journal article (peer-reviewed)abstract
- The study characterises a range of advanced MAST carbons derived from pyrolysed porous phenolic resins for use in biological applications, considering how the porosity of the carbons impacts both the methods used to assess potential cytotoxicity and the removal of biological molecules relevant to kidney disease. The large surface area and pore volume available for adsorption make both the microporous and the mesoporous MAST carbons suitable for creatinine removal but not for removal of the small but highly water soluble urea. However, only the highly adsorbent MAST carbons with meso- and macroporosity were able to remove the high molecular weight inflammatory cytokine IL-6. It is the adsorption of the larger biological toxins, represented by IL-6 in this study and not removed by purely microporous carbons or in current haemodialysis therapy, which could most significantly contribute to the augmentation of current haemoperfusion therapy.
|
|
| 23. |
|
|
| 24. |
- Andrade, S. C. S., et al.
(author)
-
Disentangling ribbon worm relationships: multi-locus analysis supports traditional classification of the phylum Nemertea
- 2012
-
In: Cladistics. - : Wiley. - 0748-3007. ; 28:2, s. 141-159
-
Journal article (peer-reviewed)abstract
- The phylogenetic relationships of selected members of the phylum Nemertea are explored by means of six markers amplified from the genomic DNA of freshly collected specimens (the nuclear 18S rRNA and 28S rRNA genes, histones H3 and H4, and the mitochondrial genes 16S rRNA and cytochrome c oxidase subunit I). These include all previous markers and regions used in earlier phylogenetic analyses of nemerteans, therefore acting as a scaffold to which one could pinpoint any previously published study. Our results, based on analyses of static and dynamic homology concepts under probabilistic and parsimony frameworks, agree in the non-monophyly of Palaeonemertea and in the monophyly of Heteronemerta and Hoplonemertea. The position of Hubrechtella and the Pilidiophora hypothesis are, however, sensitive to analytical method, as is the monophyly of the non-hubrechtiid palaeonemerteans. Our results are, however, consistent with the main division of Hoplonemertea into Polystilifera and Monostilifera, the last named being divided into Cratenemertea and Distromatonemertea, as well as into the main division of Heteronemertea into Baseodiscus and the remaining species. The study also continues to highlight the deficient taxonomy at the family and generic level within Nemertea and sheds light on the areas of the tree that require further refinement.
|
|
| 25. |
- Axelsson, Malin, et al.
(author)
-
Lived experiences: a focus group pilot study within the MentALLY project of mental healthcare among European users
- 2020
-
In: BMC Health Services Research. - : Springer Science and Business Media LLC. - 1472-6963. ; 20:1
-
Journal article (peer-reviewed)abstract
- BackgroundMental healthcare is an important component in societies' response to mental health problems. Although the World Health Organization highlights availability, accessibility, acceptability and quality of healthcare as important cornerstones, many Europeans lack access to mental healthcare of high quality. Qualitative studies exploring mental healthcare from the perspective of people with lived experiences would add to previous research and knowledge by enabling in-depth understanding of mental healthcare users, which may be of significance for the development of mental healthcare. Therefore, the aim of the current study was to describe experiences of mental healthcare among adult Europeans with mental health problems.MethodIn total, 50 participants with experiences of various mental health problems were recruited for separate focus group interviews in each country. They had experiences from both the private and public sectors, and with in- and outpatient mental healthcare. The focus group interviews (N=7) were audio recorded, transcribed verbatim and analysed through thematic analysis. The analysis yielded five themes and 13 subthemes.ResultsThe theme Seeking and trying to find help contained three subthemes describing personal thresholds for seeking professional help, not knowing where to get help, and the importance of receiving help promptly. The theme Awaiting assessment and treatment contained two subthemes including feelings of being prioritized or not and feelings of being abandoned during the often-lengthy referral process. The theme Treatment: a plan with individual parts contained three subthemes consisting of demands for tailored treatment plans in combination with medications and human resources and agreement on treatment. The theme Continuous and respectful care relationship contained two subthemes describing the importance of continuous care relationships characterised by empathy and respect. The theme Suggestions for improvements contained three subthemes highlighting an urge to facilitate care contacts and to increase awareness of mental health problems and a wish to be seen as an individual with potential.ConclusionFacilitating contacts with mental healthcare, a steady contact during the referral process, tailored treatment and empathy and respect are important aspects in efforts to improve mental healthcare. Recommendations included development of collaborative practices between stakeholders in order to increase general societal awareness of mental health problems.
|
|
| 26. |
- Birke-Sorensen, H., et al.
(author)
-
Evidence-based recommendations for negative pressure wound therapy: Treatment variables (pressure levels, wound filler and contact layer) - Steps towards an international consensus
- 2011
-
In: Journal of Plastic, Reconstructive and Aesthetic Surgery. - : Elsevier BV. - 1878-0539 .- 1748-6815. ; 64, s. 1-16
-
Research review (peer-reviewed)abstract
- Negative pressure wound therapy (NPWT) is becoming a commonplace treatment in many clinical settings. New devices and dressings are being introduced. Despite widespread adoption, there remains uncertainty regarding several aspects of NPWT use. To respond to these gaps, a global expert panel was convened to develop evidence-based recommendations describing the use of NPWT. In a previous communication, we have reviewed the evidence base for the use of NPWT within trauma and reconstructive surgery. In this communication, we present results of the assessment of evidence relating to the different NPWT treatment variables: different wound fillers (principally foam and gauze); when to use a wound contact layer; different pressure settings; and the impact of NPWT on bacterial bioburden. Evidence-based recommendations were obtained by a systematic review of the literature, grading of evidence and drafting of the recommendations by a global expert panel. Evidence and recommendations were graded according to the Scottish Intercollegiate Guidelines Network (SIGN) classification system. In general, there is relatively weak evidence on which to base recommendations for any one NPWT treatment variable over another. Overall, 14 recommendations were developed: five for the choice of wound filler and wound contact layer, four for choice of pressure setting and five for use of NPWT in infected wounds. With respect to bioburden, evidence suggests that reduction of bacteria in wounds is not a major mode of action of NPWT. (C) 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
|
|
| 27. |
- Del Chiaro, M, et al.
(author)
-
European evidence-based guidelines on pancreatic cystic neoplasms
- 2018
-
In: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 67:5, s. 789-804
-
Journal article (peer-reviewed)abstract
- Evidence-based guidelines on the management of pancreatic cystic neoplasms (PCN) are lacking. This guideline is a joint initiative of the European Study Group on Cystic Tumours of the Pancreas, United European Gastroenterology, European Pancreatic Club, European-African Hepato-Pancreato-Biliary Association, European Digestive Surgery, and the European Society of Gastrointestinal Endoscopy. It replaces the 2013 European consensus statement guidelines on PCN. European and non-European experts performed systematic reviews and used GRADE methodology to answer relevant clinical questions on nine topics (biomarkers, radiology, endoscopy, intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystic neoplasm, rare cysts, (neo)adjuvant treatment, and pathology). Recommendations include conservative management, relative and absolute indications for surgery. A conservative approach is recommended for asymptomatic MCN and IPMN measuring <40 mm without an enhancing nodule. Relative indications for surgery in IPMN include a main pancreatic duct (MPD) diameter between 5 and 9.9 mm or a cyst diameter ≥40 mm. Absolute indications for surgery in IPMN, due to the high-risk of malignant transformation, include jaundice, an enhancing mural nodule >5 mm, and MPD diameter >10 mm. Lifelong follow-up of IPMN is recommended in patients who are fit for surgery. The European evidence-based guidelines on PCN aim to improve the diagnosis and management of PCN.
|
|
| 28. |
- Grotzinger, J.P., et al.
(author)
-
A habitable fluvio-lacustrine environment at Yellowknife Bay, Gale Crater, Mars
- 2014
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 343:6169
-
Journal article (peer-reviewed)abstract
- The Curiosity rover discovered fine-grained sedimentary rocks, which are inferred to represent an ancient lake and preserve evidence of an environment that would have been suited to support a martian biosphere founded on chemolithoautotrophy. This aqueous environment was characterized by neutral pH, low salinity, and variable redox states of both iron and sulfur species. Carbon, hydrogen, oxygen, sulfur, nitrogen, and phosphorus were measured directly as key biogenic elements; by inference, phosphorus is assumed to have been available. The environment probably had a minimum duration of hundreds to tens of thousands of years. These results highlight the biological viability of fluvial-lacustrine environments in the post-Noachian history of Mars.
|
|
| 29. |
- Gullbo, Joachim, et al.
(author)
-
Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment
- 2011
-
In: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 82:2, s. 139-147
-
Journal article (peer-reviewed)abstract
- Primary cultures of patient tumor cells (PCPTC) have been used for prediction of diagnosis-specific activity and individual patient response to anticancer drugs, but have not been utilized as a model for identification of novel drugs in high throughput screening. In the present study, ovarian carcinoma cells from three patients were tested in response to a library of 3000 chemically diverse compounds. Eight hits were retrieved after counter screening using normal epithelial cells, and one of the two structurally related hit compounds was selected for further preclinical evaluation. This compound, designated VLX 50, demonstrated a broad spectrum of activity when tested in a panel of PCPTCs representing different forms of leukemia and solid tumors and displayed a high tumor to normal cell activity. VLX 50 induced delayed cell death with some features of classical apoptosis. Significant in vivo activity was confirmed on primary cultures of human ovarian carcinoma cells in mice using the hollow fiber model. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. This query signature was analyzed using the Gene Set Enrichment Analysis and the Connectivity Map database. Strong connections to hypoxia inducible factor 1 and iron chelators were retrieved. The mechanistic hypothesis of intracellular iron depletion leading to hypoxia signaling was confirmed by a series of experiments. The results indicate the feasibility of using PCPTC for cancer drug screening and that intracellular iron depletion could be a potentially important strategy for cancer therapy.
|
|
| 30. |
- Knaapila, Matti, et al.
(author)
-
A new small-angle X-ray scattering set-up on the crystallography beamline I711 at MAX-lab.
- 2009
-
In: Journal of Synchrotron Radiation. - 1600-5775. ; 16:Pt 4, s. 498-504
-
Journal article (peer-reviewed)abstract
- A small-angle X-ray scattering (SAXS) set-up has recently been developed at beamline I711 at the MAX II storage ring in Lund (Sweden). An overview of the required modifications is presented here together with a number of application examples. The accessible q range in a SAXS experiment is 0.009-0.3 A(-1) for the standard set-up but depends on the sample-to-detector distance, detector offset, beamstop size and wavelength. The SAXS camera has been designed to have a low background and has three collinear slit sets for collimating the incident beam. The standard beam size is about 0.37 mm x 0.37 mm (full width at half-maximum) at the sample position, with a flux of 4 x 10(10) photons s(-1) and lambda = 1.1 A. The vacuum is of the order of 0.05 mbar in the unbroken beam path from the first slits until the exit window in front of the detector. A large sample chamber with a number of lead-throughs allows different sample environments to be mounted. This station is used for measurements on weakly scattering proteins in solutions and also for colloids, polymers and other nanoscale structures. A special application supported by the beamline is the effort to establish a micro-fluidic sample environment for structural analysis of samples that are only available in limited quantities. Overall, this work demonstrates how a cost-effective SAXS station can be constructed on a multipurpose beamline.
|
|
| 31. |
- Lindgren, Hanna S., et al.
(author)
-
Putaminal Upregulation of FosB/ΔFosB-Like Immunoreactivity in Parkinson's Disease Patients with Dyskinesia
- 2011
-
In: Journal of Parkinson's Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 1:4, s. 347-357
-
Journal article (peer-reviewed)abstract
- The transcription factor FosB is a mediator of maladaptive neuroplasticity in animal models of Parkinson´s disease (PD) and L-DOPA-induced dyskinesia. Using an antibody that recognizes all known isoforms of FosB and FosB, we have examined the expression of these proteins in post-mortem basal ganglia sections from PD patients. The patient cases were classified as being dyskinetic or non-dyskinetic based on their clinical records. Sections from neurologically healthy controls were also included in the study. Compared to both controls and non-dyskinetic cases, the dyskinetic group showed a higher density of FosB/ FosB-immunopositive cells in the posterior putamen, which represents the motor region of the striatum in primates. In contrast, the number of FosB/ FosB-positive cells did not differ significantly among the groups in the caudate, a region primarily involved with the processing of cognitive and limbic-related information. Only sparse FosB/ FosB immunoreactivity was found in the in the pallidum externum and internum, and no significant group differences were detected in these nuclei. The putaminal elevation of FosB/ FosB-like immunoreactivity in patients who had been affected by L-DOPA-induced dyskinesia is consistent with results from both rat and non-human primate models of this movement disorder. The present findings support the hypothesis of an involvement of FosB-related transcription factors in the molecular mechanisms of L-DOPA-induced dyskinesia.
|
|
| 32. |
- Rinaldi, S, et al.
(author)
-
Physical activity, sex steroid, and growth factor concentrations in pre- and post-menopausal women : a cross-sectional study within the EPIC cohort
- 2014
-
In: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 0957-5243 .- 1573-7225. ; 25:1, s. 111-124
-
Journal article (peer-reviewed)abstract
- Increased physical activity (PA) is associated with a reduced risk of several cancers. PA may reduce cancer risk by changing endogenous hormones levels, but relatively little research has focused on this topic. The purpose of this study was to elucidate the relation between PA and endogenous hormone concentrations. A cross-sectional analysis of 798 pre- and 1,360 post-menopausal women included as controls in case-control studies on endogenous hormones (steroids, progesterone, sex-hormone-binding globulin (SHBG), and growth factors) levels, and cancer risk nested within European Prospective Investigation into Cancer and Nutrition cohort was performed. Multivariate regression analyses were performed to compare geometric mean levels of hormones and SHBG by categories of PA. In pre-menopausal women, active women had 19 % significantly lower concentrations of androstenedione, 14 % lower testosterone, and 20 % lower free testosterone than inactive women, while no differences were observed for estrogens, progesterone, SHBG, and growth factors. In post-menopausal women, active women had 18 % significantly lower estradiol and 20 % lower free estradiol concentrations than inactive women, while no differences were observed for the other hormones and SHBG. More vigorous forms of physical activity were associated with higher insulin-like growth factor-I concentrations. Adjustment for body mass index did not alter the associations. Overall, the percentage of variance in hormone concentrations explained by PA levels was < 2 %. Our results support the hypothesis of an influence, although small in magnitude, of PA on sex hormone levels in blood, independent of body size.
|
|
| 33. |
- Runkel, N., et al.
(author)
-
Evidence-based recommendations for the use of Negative Pressure Wound Therapy in traumatic wounds and reconstructive surgery: Steps towards an international consensus
- 2011
-
In: Injury. - 1879-0267. ; 42:Suppl. 1, s. 1-12
-
Journal article (peer-reviewed)abstract
- Negative pressure wound therapy (NPWT) has become widely adopted over the last 15 years and over 1000 peer reviewed publications are available describing its use. Despite this, there remains uncertainty regarding several aspects of usage. In order to respond to this gap a global expert panel was convened to develop evidence-based recommendations describing the use of NPWT. In this paper the results of the study of evidence in traumatic wounds (including soft tissue defects, open fractures and burns) and reconstructive procedures (including flaps and grafts) are reported. Evidence-based recommendations were obtained by a systematic review of the literature, grading of evidence, drafting of the recommendations by a global expert panel, followed by a formal consultative consensus development program in which 422 independent healthcare professionals were able to agree or disagree with the recommendations. The criteria for agreement were set at 80% approval. Evidence and recommendations were graded according to the SIGN (Scottish Intercollegiate Guidelines Network) classification system. Twelve recommendations were developed in total; 4 for soft tissue trauma and open fracture injuries, 1 for burn injuries, 3 for flaps and 4 for skin grafts. The present evidence base is strongest for the use of NPWT on skin grafts and weakest as a primary treatment for burns. In the consultative process, 11/12 of the proposed recommendations reached the 80% agreement threshold. The development of evidence-based recommendations for NPWT with direct validation from a large group of practicing clinicians offers a broader basis for consensus than work by an expert panel alone. (C) 2011 Elsevier Ltd. All rights reserved.
|
|
| 34. |
- Taslimi, Y., et al.
(author)
-
Profiling inflammatory response in lesions of cutaneous leishmaniasis patients using a non-invasive sampling method combined with a high-throughput protein detection assay
- 2020
-
In: Cytokine. - : Elsevier BV. - 1043-4666. ; 130:June
-
Journal article (peer-reviewed)abstract
- Background: Cutaneous leishmaniasis (CL) is an infection caused by Leishmania (L.) protozoa transmitted through the bite of infected sand fly. Previously, invasive sampling of blood and skin along with low throughput methods were used for determination of inflammatory response in CL patients. Aims/Methodology: We established a novel approach based on a non-invasive adhesive tape-disc sampling combined with a powerful multiplexing technique called proximity extension assay for profiling 92 inflammatory cytokines, chemokines and surface molecules in the lesions of CL patients infected with L. tropica. Sample collection was done non-invasively by using adhesive tape-discs from lesion and normal skin of 33 L. tropica positive patients. Results: Out of 92 inflammatory proteins, the level of 34 proteins was significantly increased in the lesions of CL patients compared to their normal skin. This includes the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL5, CXCL9, CXCL10 and CXCL11, together with the interleukins IL-6, IL-8, IL-18, LIF and OSM. The remaining significantly changed inflammatory proteins include 7 surface molecules and receptors: CD5, CD40, CDCP1, 4E-BP1, TNFRSF9, IL-18R1 and OPG as well as 16 other cytokines and proteins: MMP-1, CSF-1, VEGFA, uPA, EN-RAGE, LAP TGF-beta 1, HGF, MMP-10, CASP-8, TNFSF14, STAMPB, ADA, TRAIL and ST1A1. Further, 13 proteins showed an increasing trend, albeit not statistically significant, in the CL lesions, including TGF-alpha, CCL23, MCP-2, IL-12B, CXCL6, IL-24, FGF-19, TNF beta, CD6, TRANCE, IL10, SIR2 and CCL20. Conclusion: We herein report a novel approach based on a non-invasive sampling method combined with the high-throughput protein assay for profiling inflammatory proteins in CL lesions. Using this approach, we could profile inflammatory proteins in the lesions from CL patients. This new non-invasive approach may have implications for studying skin inflammatory mediators in CL and other skin disorders.
|
|
| 35. |
- Vig, S., et al.
(author)
-
Evidence-based recommendations for the use of negative pressure wound therapy in chronic wounds: Steps towards an international consensus
- 2011
-
In: Journal of Tissue Viability. - : Elsevier BV. - 1876-4746 .- 0965-206X. ; 20, s. 1-18
-
Research review (peer-reviewed)abstract
- Aim: Negative Pressure Wound Therapy (NPWT) has become widely adopted over the last 15 years and over 1000 peer-reviewed publications are available describing its use. Despite this, there remains uncertainty regarding several aspects of usage. In order to respond to this gap a global expert panel was convened to develop evidence-based recommendations describing the use of NPWT. In this communication the results of the study of evidence in chronic wounds including pressure ulcers, diabetic foot ulcers (DFU), venous leg ulcers (VLU), and ischaemic lower limb wounds are reported. Methods: Evidence-based recommendations were obtained by a systematic review of the literature, grading of evidence, drafting of the recommendations by a global expert panel followed by a formal consultative consensus development program in which 422 independent healthcare professionals were able to agree or disagree with the recommendations. The criteria for agreement were set at 80% agreement. Evidence and recommendations were graded according to the SIGN (Scottish Intercollegiate Guidelines Network) classification system. Results: The primary treatment goal of NPWT in most chronic wounds is to achieve wound closure (either by secondary intention or preparing the wound for surgical closure). Secondary goals commonly include: to reduce wound dimensions, and to improve the quality of the wound bed. Thirteen evidence based recommendations were developed in total to address these treatment goals; 4 for pressure ulcers, 4 for DFU, 3 for ischaemic lower limb wounds and 2 for VLU. Conclusion: The present evidence base is strongest for the use of NPWT in non-ischaemic DFU and weakest in VLU. The development of evidence-based recommendations for NPWT with direct validation from a large group of practicing clinicians offers a broader basis for consensus than work by an expert panel alone. (c) 2011 Published by Elsevier Ltd on behalf of Tissue Viability Society.
|
|
| 36. |
- Yammine, S.G., et al.
(author)
-
Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition
- 2023
-
In: BMC Cancer. - : BioMed Central (BMC). - 1471-2407. ; 23:1
-
Journal article (peer-reviewed)abstract
- Background: Diet may impact important risk factors for endometrial cancer such as obesity and inflammation. However, evidence on the role of specific dietary factors is limited. We investigated associations between dietary fatty acids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).Methods: This analysis includes 1,886 incident endometrial cancer cases and 297,432 non-cases. All participants were followed up for a mean of 8.8 years. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of endometrial cancer across quintiles of individual fatty acids estimated from various food sources quantified through food frequency questionnaires in the entire EPIC cohort. The false discovery rate (q-values) was computed to control for multiple comparisons.Results: Consumption of n-6 γ-linolenic acid was inversely associated with endometrial cancer risk (HR comparing 5th with 1st quintileQ5−Q1=0.77, 95% CI = 0.64; 0.92, ptrend=0.01, q-value = 0.15). This association was mainly driven by γ-linolenic acid derived from plant sources (HRper unit increment=0.94, 95%CI= (0.90;0.98), p = 0.01) but not from animal sources (HRper unit increment= 1.00, 95%CI = (0.92; 1.07), p = 0.92). In addition, an inverse association was found between consumption of n-3 α-linolenic acid from vegetable sources and endometrial cancer risk (HRper unit increment= 0.93, 95%CI = (0.87; 0.99), p = 0.04). No significant association was found between any other fatty acids (individual or grouped) and endometrial cancer risk.Conclusion: Our results suggest that higher consumption of γ-linolenic acid and α-linoleic acid from plant sources may be associated with lower risk of endometrial cancer.
|
|
| 37. |
- Yang, D. P., et al.
(author)
-
Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection
- 2022
-
In: Cell. - : Elsevier BV. - 0092-8674. ; 185:22
-
Journal article (peer-reviewed)abstract
- Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demon-strate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.
|
|
| 38. |
|
|
| 39. |
- Andersson, Claes, et al.
(author)
-
Mebendazole is unique among tubulin-active drugs in activating the MEK-ERK pathway
- 2020
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Journal article (peer-reviewed)abstract
- We recently showed that the anti-helminthic compound mebendazole (MBZ) has immunomodulating activity in monocyte/macrophage models and induces ERK signalling. In the present study we investigated whether MBZ induced ERK activation is shared by other tubulin binding agents (TBAs) and if it is observable also in other human cell types. Curated gene signatures for a panel of TBAs in the LINCS Connectivity Map (CMap) database showed a unique strong negative correlation of MBZ with MEK/ERK inhibitors indicating ERK activation also in non-haematological cell lines. L1000 gene expression signatures for MBZ treated THP-1 monocytes also connected negatively to MEK inhibitors. MEK/ERK phosphoprotein activity testing of a number of TBAs showed that only MBZ increased the activity in both THP-1 monocytes and PMA differentiated macrophages. Distal effects on ERK phosphorylation of the substrate P90RSK and release of IL1B followed the same pattern. The effect of MBZ on MEK/ERK phosphorylation was inhibited by RAF/MEK/ERK inhibitors in THP-1 models, CD3/IL2 stimulated PBMCs and a MAPK reporter HEK-293 cell line. MBZ was also shown to increase ERK activity in CD4+ T-cells from lupus patients with known defective ERK signalling. Given these mechanistic features MBZ is suggested suitable for treatment of diseases characterized by defective ERK signalling, notably difficult to treat autoimmune diseases.
|
|
| 40. |
- ANDRADE, S.C.S, et al.
(author)
-
A transcriptomic approach to ribbon worm systematics (Nemertea): resolving the Pilidiophora problem.
- 2014
-
In: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 31:12, s. 3206-3215
-
Journal article (peer-reviewed)abstract
- Resolving the deep relationships of ancient animal lineages has proven difficult using standard Sanger-sequencing approaches with a handful of markers. We thus reassess the relatively well-studied phylogeny of the phylum Nemertea (ribbon worms)—for which the targeted gene approaches had resolved many clades but had left key phylogenetic gaps—by using a phylogenomic approach using Illumina-based de novo assembled transcriptomes and automatic orthology prediction methods. The analysis of a concatenated data set of 2,779 genes (411,138 amino acids) with about 78% gene occupancy and a reduced version with 95% gene occupancy, under evolutionary models accounting or not for site-specific amino acid replacement patterns results in a well-supported phylogeny that recovers all major accepted nemertean clades with the monophyly of Heteronemertea, Hoplonemertea, Monostilifera, being well supported. Significantly, all the ambiguous patterns inferred from Sanger-based approaches were resolved, namely the monophyly of Palaeonemertea and Pilidiophora. By testing for possible conflict in the analyzed supermatrix, we observed that concatenation was the best solution, and the results of the analyses should settle prior debates on nemertean phylogeny. The study highlights the importance, feasibility, and completeness of Illumina-based phylogenomic data matrices.
|
|
| 41. |
- Bahrami, F., et al.
(author)
-
Blood transcriptional profiles distinguish different clinical stages of cutaneous leishmaniasis in humans
- 2022
-
In: Molecular Immunology. - : Elsevier BV. - 0161-5890. ; 149, s. 165-173
-
Journal article (peer-reviewed)abstract
- Cutaneous leishmaniasis (CL) is a neglected tropical disease with severe morbidity and socioeconomic sequelae. A better understanding of underlying immune mechanisms that lead to different clinical outcomes of CL could inform the rational design of intervention measures. While transcriptomic analyses of CL lesions were recently reported by us and others, there is a dearth of information on the expression of immune-related genes in the blood of CL patients. Herein, we investigated immune-related gene expression in whole blood samples collected from individuals with different clinical stages of CL along with healthy volunteers in an endemic CL region where Leishmania (L.) tropica is prevalent. Study participants were categorized into asymptomatic (LST+) and healthy uninfected (LST-) groups based on their leishmanin skin test (LST). Whole blood PAXgene samples were collected from volunteers, who had healed CL lesions, and patients with active L. tropica cutaneous lesions. Quality RNA extracted from 57 blood samples were subjected to Dual-color reverse-transcription multiplex ligation-dependent probe amplification (dcRT-MLPA) assay for profiling 144 immune-related genes. Results show significant changes in the expression of genes involved in interferon signaling pathway in the blood of active CL patients, asymptomatics and healed individuals. Nonetheless, distinct profiles for several immune-related genes were identified in the healed, the asymptomatic, and the CL patients compared to the healthy controls. Among others, IFI16 and CCL11 were found as immune transcript signatures for the healed and the asymptomatic individuals, respectively. These results warrant further exploration to pinpoint novel blood biomarkers for different clinical stages of CL.
|
|
| 42. |
- Beecham, Ashley H, et al.
(author)
-
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
-
In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
-
Journal article (peer-reviewed)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.
|
|
| 43. |
- Bernson, Elin, 1987, et al.
(author)
-
Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2-Based Immunotherapy in Acute Myeloid Leukemia
- 2018
-
In: Cancer Immunology Research. - : American Association for Cancer Research (AACR). - 2326-6066 .- 2326-6074. ; 6:9, s. 1110-1119
-
Journal article (peer-reviewed)abstract
- Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to affect favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of patients with AML not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 nontransplanted AML patients who were receiving relapse-prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996). CMV seropositivity correlated negatively with leukemia-free and overall survival of patients receiving HDC/IL2, but did not correlate with outcomes in a contemporary control cohort. Analysis of outcome after stratification of patients based on concordant or discordant killer immunoglobulin-like receptor (KIR) and HLA genotypes implied that the negative impact of CMV seropositivity was restricted to patients lacking a ligand to inhibitory KIRs (iKIR). Previous CMV infection was also associated with fewer NK cells expressing only nonself iKIRs (NS-iKIR). We propose that CMV-driven NK cell education depletes the population of NS-iKIR NK cells, which in turn reduces the clinical benefit of relapse-preventive immunotherapy in AML.
|
|
| 44. |
- Bhoo-Pathy, Nirmala, et al.
(author)
-
Intake of Coffee, Decaffeinated Coffee, or Tea Does Not Affect Risk for Pancreatic Cancer : Results From the European Prospective Investigation into Nutrition and Cancer Study
- 2013
-
In: Clinical Gastroenterology and Hepatology. - : Elsevier. - 1542-3565 .- 1542-7714. ; 11:11, s. 1486-1492
-
Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: Few modifiable risk factors have been implicated in the etiology of pancreatic cancer. There is little evidence for the effects of caffeinated coffee, decaffeinated coffee, or tea intake on risk of pancreatic cancer. We investigated the association of total coffee, caffeinated coffee, decaffeinated coffee, and tea consumption with risk of pancreatic cancer.METHODS: This study was conducted within the European Prospective Investigation into Nutrition and Cancer cohort, comprising male and female participants from 10 European countries. Between 1992 and 2000, there were 477,312 participants without cancer who completed a dietary questionnaire, and were followed up to determine pancreatic cancer incidence. Coffee and tea intake was calibrated with a 24-hour dietary recall. Adjusted hazard ratios (HRs) were computed using multivariable Cox regression.RESULTS: During a mean follow-up period of 11.6 y, 865 first incidences of pancreatic cancers were reported. When divided into fourths, neither total intake of coffee (HR, 1.03; 95% confidence interval [CI], 0.83-1.27; high vs low intake), decaffeinated coffee (HR, 1.12; 95% CI, 0.76-1.63; high vs low intake), nor tea were associated with risk of pancreatic cancer (HR, 1.22, 95% CI, 0.95-1.56; high vs low intake). Moderately low intake of caffeinated coffee was associated with an increased risk of pancreatic cancer (HR, 1.33; 95% CI, 1.02-1.74), compared with low intake. However, no graded dose response was observed, and the association attenuated after restriction to histologically confirmed pancreatic cancers.CONCLUSIONS: Based on an analysis of data from the European Prospective Investigation into Nutrition and Cancer cohort, total coffee, decaffeinated coffee, and tea consumption are not related to the risk of pancreatic cancer.
|
|
| 45. |
- Blom, Kristin, et al.
(author)
-
Mebendazole-induced M1 polarisation of THP-1 macrophages may involve DYRK1B inhibition
- 2019
-
In: BMC Research Notes. - : Springer Nature. - 1756-0500. ; 12:1
-
Journal article (peer-reviewed)abstract
- Objective: We recently showed that the anti-helminthic compound mebendazole (MBZ) has immunomodulating activity by inducing a M2 to M1 phenotype switch in monocyte/macrophage models. In the present study we investigated the potential role of protein kinases in mediating this effect.Results: MBZ potently binds and inhibits Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B) with a Kd and an IC50 of 7 and 360 nM, respectively. The specific DYRK1B inhibitor AZ191 did not mimic the cytokine release profile of MBZ in untreated THP-1 monocytes. However, in THP-1 cells differentiated into macrophages, AZ191 strongly induced a pro-inflammatory cytokine release pattern similar to MBZ and LPS/IFNγ. Furthermore, like MBZ, AZ191 increased the expression of the M1 marker CD80 and decreased the M2 marker CD163 in THP-1 macrophages. In this model, AZ191 also increased phospho-ERK activity although to a lesser extent compared to MBZ. Taken together, the results demonstrate that DYRK1B inhibition could, at least partly, recapitulate immune responses induced by MBZ. Hence, DYRK1B inhibition induced by MBZ may be part of the mechanism of action to switch M2 to M1 macrophages.
|
|
| 46. |
- Bloom, A. C., et al.
(author)
-
Deletion of the membrane complement inhibitor CD59a drives age and gender-dependent alterations to bone phenotype in mice
- 2016
-
In: Bone. - : Elsevier BV. - 8756-3282. ; 84, s. 253-261
-
Journal article (peer-reviewed)abstract
- Degenerative joint diseases such as osteoarthritis are characterised by aberrant region-specific bone formation and abnormal bone mineral content. A recent study suggested a role for the complement membrane attack complex in experimental models of osteoarthritis. Since CD59a is the principal regulator of the membrane attack complex in mice, we evaluated the impact of CD59a gene deletion upon maintenance of bone architecture. In vivo bone morphology analysis revealed that male CD59a-deficient mice have increased femur length and cortical bone volume, albeit with reduced bone mineral density. However, this phenomenon was not observed in female mice. Histomorphometric analysis of the trabecular bone showed increased rates of bone homeostasis, with both increased bone resorption and mineral apposition rate in CD59a-deficient male mice. When bone cells were studied in isolation, in vitro osteoclastogenesis was significantly increased in male CD59a-deficient mice, although osteoblast formation was not altered. Our data reveal, for the first time, that CD59a is a regulator of bone growth and homeostasis. CD59a ablation in male mice results in longer and wider bones, but with less density, which is likely a major contributing factor for their susceptibility to osteoarthritis. These findings increase our understanding of the role of complement regulation in degenerative arthritis.
|
|
| 47. |
- Bonagas, Nadilly, et al.
(author)
-
Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
-
In: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
-
Journal article (peer-reviewed)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
|
|
| 48. |
- Burgman, A., et al.
(author)
-
The ESSnuSB Design Study: Overview and Future Prospects
- 2023
-
In: Universe. - : MDPI. - 2218-1997. ; 9:8
-
Research review (peer-reviewed)abstract
- ESSnuSB is a design study for an experiment to measure the CP violation in the leptonic sector at the second neutrino oscillation maximum using a neutrino beam driven by the uniquely powerful ESS linear accelerator. The reduced impact of systematic errors on sensitivity at the second maximum allows for a very precise measurement of the CP violating parameter. This review describes the fundamental advantages of measurement at the second maximum, the necessary upgrades to the ESS linac in order to produce a neutrino beam, the near and far detector complexes, and the expected physics reach of the proposed ESSnuSB experiment, concluding with the near future developments aimed at the project realization.
|
|
| 49. |
|
|
| 50. |
- Cinato, Mathieu, et al.
(author)
-
Cardiac Plin5 interacts with SERCA2 and promotes calcium handling and cardiomyocyte contractility
- 2023
-
In: Life Science Alliance. - : Life Science Alliance, LLC. - 2575-1077. ; 6:4
-
Journal article (peer-reviewed)abstract
- The adult heart develops hypertrophy to reduce ventricular wall stress and maintain cardiac function in response to an increased workload. Although pathological hypertrophy generally prog-resses to heart failure, physiological hypertrophy may be car-dioprotective. Cardiac-specific overexpression of the lipid-droplet protein perilipin 5 (Plin5) promotes cardiac hypertrophy, but it is unclear whether this response is beneficial. We analyzed RNA -sequencing data from human left ventricle and showed that car-diac PLIN5 expression correlates with up-regulation of cardiac contraction-related processes. To investigate how elevated cardiac Plin5 levels affect cardiac contractility, we generated mice with cardiac-specific overexpression of Plin5 (MHC-Plin5 mice). These mice displayed increased left ventricular mass and cardiomyocyte size but preserved heart function. Quantitative proteomics identified sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) as a Plin5-interacting protein. In situ proximity ligation assay further confirmed the Plin5/SERCA2 interaction. Live imaging showed in-creases in intracellular Ca2+ release during contraction, Ca2+ removal during relaxation, and SERCA2 function in MHC-Plin5 versus WT cardiomyocytes. These results identify a role of Plin5 in improving cardiac contractility through enhanced Ca2+ signaling.
|
|
