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- Thompson, Paul M., et al.
(författare)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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Ingår i: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Tidskriftsartikel (refereegranskat)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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- Schoenrock, A., et al.
(författare)
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Efficient prediction of human protein-protein interactions at a global scale
- 2014
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Ingår i: Bmc Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Our knowledge of global protein-protein interaction (PPI) networks in complex organisms such as humans is hindered by technical limitations of current methods. Results: On the basis of short co-occurring polypeptide regions, we developed a tool called MP-PIPE capable of predicting a global human PPI network within 3 months. With a recall of 23% at a precision of 82.1%, we predicted 172,132 putative PPIs. We demonstrate the usefulness of these predictions through a range of experiments. Conclusions: The speed and accuracy associated with MP-PIPE can make this a potential tool to study individual human PPI networks (from genomic sequences alone) for personalized medicine.
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- Bruhn, Sören, et al.
(författare)
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A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy
- 2014
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 6:218
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Tidskriftsartikel (refereegranskat)abstract
- The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (T(H)2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.
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- Bushnell, David L., et al.
(författare)
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90Y-edotreotide for metastatic carcinoid refractory to octreotide
- 2010
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 28:10, s. 1652-1659
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using (90)Y-edotreotide to treat symptomatic patients with carcinoid tumors. PATIENTS AND METHODS: Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) (90)Y-edotreotide each, once every 6 weeks. RESULTS: Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms assessed. Median progression-free survival was significantly greater (P = .03) for the 38 patients who had durable diarrhea improvement than the 18 patients who did not (18.2 v 7.9 months, respectively). Adverse events (AEs) were reported in 96.7% (87 of 90) of patients. These AEs consisted primarily of reversible GI events (76 of 90), which could be caused in part by concomitant administration of amino acid solution given to reduce radiation exposure to the kidneys. There was one case each of grade 3 oliguria and grade 4 renal failure, each lasting 6 days. CONCLUSION: (90)Y-edotreotide treatment improved symptoms associated with malignant carcinoid among subjects with no treatment alternatives. Treatment was well-tolerated and had an acceptable expected AE profile.
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| 6. |
- White, Matt A., et al.
(författare)
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New Australovenator Hind Limb Elements Pertaining to the Holotype Reveal the Most Complete Neovenatorid Leg
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7, s. e68649-
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Tidskriftsartikel (refereegranskat)abstract
- We report new skeletal elements pertaining to the same individual which represents the holotype of Australovenator wintonensis, from the 'Matilda Site' in the Winton Formation (Upper Cretaceous) of western Queensland. The discovery of these new elements means that the hind limb of Australovenator is now the most completely understood hind limb among Neovenatoridae. The new hind limb elements include: the left fibula; left metatarsal IV; left pedal phalanges I-2, II-1, III-4, IV-2, IV-3; and right pedal phalanges, II-2 and III-1. The detailed descriptions are supported with three dimensional figures. These coupled with the completeness of the hind limb will increase the utility of Australovenator in comparisons with less complete neovenatorid genera. These specimens and the previously described hind limb elements of Australovenator are compared with other theropods classified as neovenatorids (including Neovenator, Chilantaisaurus, Fukuiraptor, Orkoraptor and Megaraptor). Hind limb length proportion comparisons indicate that the smaller neovenatorids Australovenator and Fukuiraptor possess more elongate and gracile hind limb elements than the larger Neovenator and Chilantaisaurus. Greater stride lengths to body size exist in both Fukuiraptor and Australovenator with the femur discovered to be proportionally shorter the rest of the hind limb length. Additionally Australovenator is identified as possessing the most elongate metatarsus. The metatarsus morphology varies with body size. The larger neoventorids possess a metatarsus with greater width but shorter length compared to smaller forms.
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| 7. |
- Bruhn, Sören, et al.
(författare)
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Increased expression of IRF4 and ETS1 in CD4+ cells from patients with intermittent allergic rhinitis
- 2012
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley and Sons. - 0105-4538 .- 1398-9995. ; 67:1, s. 33-40
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Tidskriftsartikel (refereegranskat)abstract
- Background: The transcription factor (TF) IRF4 is involved in the regulation of Th1, Th2, Th9, and Th17 cells, and animal studies have indicated an important role in allergy. However, IRF4 and its target genes have not been examined in human allergy. Methods: IRF4 and its target genes were examined in allergen-challenged CD4+ cells from patients with IAR, using combined gene expression microarrays and chromatin immunoprecipitation chips (ChIP-chips), computational target prediction, and RNAi knockdowns. Results: IRF4 increased in allergen-challenged CD4+ cells from patients with IAR, and functional studies supported its role in Th2 cell activation. IRF4 ChIP-chip showed that IRF4 regulated a large number of genes relevant to Th cell differentiation. However, neither Th1 nor Th2 cytokines were the direct targets of IRF4. To examine whether IRF4 induced Th2 cytokines via one or more downstream TFs, we combined gene expression microarrays, ChIP-chips, and computational target prediction and found a putative intermediary TF, namely ETS1 in allergen-challenged CD4+ cells from allergic patients. ETS1 increased significantly in allergen-challenged CD4+ cells from patients compared to controls. Gene expression microarrays before and after ETS1 RNAi knockdown showed that ETS1 induced Th2 cytokines as well as disease-related pathways. Conclusions: Increased expression of IRF4 in allergen-challenged CD4+ cells from patients with intermittent allergic rhinitis leads to activation of a complex transcriptional program, including Th2 cytokines.
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| 10. |
- Ljung, Rolf, et al.
(författare)
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Novel coagulation factor concentrates: Issues relating to their clinical implementation and pharmacokinetic assessment for optimal prophylaxis in haemophilia patients.
- 2013
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 19:4, s. 481-486
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Forskningsöversikt (refereegranskat)abstract
- Prophylaxis is considered the optimal treatment regimen for patients with severe haemophilia, and may be especially important in the prevention of joint disease. Novel coagulation factor concentrates with prolonged half-lives promise to improve patient treatment by enabling prophylaxis with less frequent dosing. With the call to individualize therapy in haemophilia, there is growing awareness of the need to use pharmacokinetic (PK) assessments to tailor prophylaxis. However, for new factor concentrates, it is not yet known which PK values will be most informative for optimizing prophylaxis. This topic was explored at the Eighth Zurich Haemophilia Forum. On the basis of our clinical experience and a discussion of the literature, we report key issues relating to the PK assessment of new coagulation factors and include suggestions on the implementation of PK data to optimize therapy. As both inter- and intra-individual variability in factor half-life have been reported, we suggest that frequent PK assessments should be conducted. However, to diminish the burden of more frequent sampling, sparser sampling strategies and the use of population modelling should be considered. Guidelines on how to assay new factor concentrates, and which PK parameters should be measured, are needed. Concerns were raised regarding the possibility of breakthrough bleeding, and current thinking on how to prevent breakthrough bleeding may no longer be appropriate. Finally, as treatment adherence may be more important to ensure that a therapeutic level of a new coagulation factor concentrate is maintained, behavioural techniques could be implemented to help to improve treatment adherence.
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