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Sökning: WFRF:(Dina C)

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51.
  • Ali, Dina, et al. (författare)
  • Anti-leukaemic effects induced by APR-246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells
  • 2016
  • Ingår i: British Journal of Haematology. - 0007-1048 .- 1365-2141. ; 174:1, s. 117-126
  • Tidskriftsartikel (refereegranskat)abstract
    • The small molecule APR-246 (PRIMA-1(MET)) is a novel drug that restores the activity of mutated and unfolded TP53 protein. However, the mechanisms of action and potential off-target effects are not fully understood. Gene expression profiling in TP53 mutant KMB3 acute myeloid leukaemia (AML) cells showed that genes which protected cells from oxidative stress to be the most up-regulated. APR-246 exposure also induced reactive oxygen species (ROS) formation and depleted glutathione in AML cells. The genes most up-regulated by APR-246, confirmed by quantitative real time polymerase chain reaction, were heme oxygenase-1 (HMOX1, also termed HO-1), SLC7A11 and RIT1. Up-regulation of HMOX1, a key regulator of cellular response to ROS, was independent of TP53 mutational status. NFE2L2 (also termed Nrf2), a master regulator of HMOX1 expression, showed transcriptional up-regulation and nuclear translocation by APR-246. Down-regulation of NFE2L2 by siRNA in AML cells significantly increased the antitumoural effects of APR-246. The PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin inhibited APR-246-induced nuclear translocation of NFE2L2 and counteracted the protective cellular responses to APR-246, resulting in synergistic cell killing together with APR-246. In conclusion, ROS induction is important for antileukaemic activities of APR-246 and inhibiting the protective response of the Nrf-2/HMOX1 axis using PI3K inhibitors, enhances the antileukaemic effects.
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52.
  • Björling, Alexander, et al. (författare)
  • Three-Dimensional Coherent Bragg Imaging of Rotating Nanoparticles
  • Ingår i: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 125:24
  • Tidskriftsartikel (refereegranskat)abstract
    • Bragg coherent diffraction imaging is a powerful strain imaging tool, often limited by beam-induced sample instability for small particles and high power densities. Here, we devise and validate an adapted diffraction volume assembly algorithm, capable of recovering three-dimensional datasets from particles undergoing uncontrolled and unknown rotations. We apply the method to gold nanoparticles which rotate under the influence of a focused coherent x-ray beam, retrieving their three-dimensional shapes and strain fields. The results show that the sample instability problem can be overcome, enabling the use of fourth generation synchrotron sources for Bragg coherent diffraction imaging to their full potential.
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53.
  • Bocchetta, Martina, et al. (författare)
  • The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey.
  • 2015
  • Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5279. ; 11:2, s. 195-206
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.
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54.
  • Bos, Isabelle, et al. (författare)
  • The frequency and influence of dementia risk factors in prodromal Alzheimer's disease
  • 2017
  • Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 56, s. 33-40
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD.
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55.
  • Bower, Matthew, et al. (författare)
  • Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database
  • Ingår i: Human Mutation. - : John Wiley and Sons. - 1059-7794. ; 33:3, s. 66-457
  • Tidskriftsartikel (refereegranskat)abstract
    • Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed.
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56.
  • della Porta, Donatella, et al. (författare)
  • The Paradoxes of Democracy and the Rule of Law
  • 2018
  • Ingår i: Rethinking Society for the 21st Century. Volume 2: Political Regulation, Governance, and Societal Transformations. Report of the International Panel on Social Progress. - Cambridge : Cambridge University Press. - 9781108399579 ; , s. 373-410
  • Bokkapitel (övrigt vetenskapligt)
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57.
  • Frayling, Timothy M., et al. (författare)
  • A Genome-Wide Scan in Families With Maturity-Onset Diabetes of the Young: Evidence for Further Genetic Heterogeneity.
  • 2003
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 1939-327X. ; 52:3, s. 872-881
  • Tidskriftsartikel (refereegranskat)abstract
    • Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non–insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15–20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of β-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169–175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.
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58.
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59.
  • Guce, Abigail I., et al. (författare)
  • Catalytic Mechanism of Human alpha-Galactosidase
  • 2010
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 285:6, s. 3625-3632
  • Tidskriftsartikel (refereegranskat)abstract
    • The enzyme alpha-galactosidase (alpha-GAL, also known as alpha-GAL A; E.C. 3.2.1.22) is responsible for the breakdown of alpha-galactosides in the lysosome. Defects in human alpha-GAL lead to the development of Fabry disease, a lysosomal storage disorder characterized by the buildup of alpha-galactosylated substrates in the tissues. alpha-GAL is an active target of clinical research: there are currently two treatment options for Fabry disease, recombinant enzyme replacement therapy (approved in the United States in 2003) and pharmacological chaperone therapy (currently in clinical trials). Previously, we have reported the structure of human alpha-GAL, which revealed the overall structure of the enzyme and established the locations of hundreds of mutations that lead to the development of Fabry disease. Here, we describe the catalytic mechanism of the enzyme derived from x-ray crystal structures of each of the four stages of the double displacement reaction mechanism. Use of a difluoro-alpha-galactopyranoside allowed trapping of a covalent intermediate. The ensemble of structures reveals distortion of the ligand into a S-1(3) skew (or twist) boat conformation in the middle of the reaction cycle. The high resolution structures of each step in the catalytic cycle will allow for improved drug design efforts on alpha-GAL and other glycoside hydrolase family 27 enzymes by developing ligands that specifically target different states of the catalytic cycle. Additionally, the structures revealed a second ligand-binding site suitable for targeting by novel pharmacological chaperones.
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60.
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