| 1. |
- Jelen, Sabina, et al.
(author)
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AQP9 Expression in Glioblastoma Multiforme Tumors Is Limited to a Small Population of Astrocytic Cells and CD15(+)/CalB(+) Leukocytes
- 2013
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9
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Journal article (peer-reviewed)abstract
- Aquaporin-9 (AQP9) is a membrane protein channel that is permeable to a range of small solutes, including glycerol, urea and nucleobases. Expression of AQP9 in normal brain is limited, while widespread AQP9 expression has previously been reported in human glioblastoma. However, the specific cellular expression of AQP9 in glioblastoma remains unclear. In this study, we have examined microarrays to corroborate AQP9 mRNA expression in glioma. These analyses suggested that AQP9 mRNA expression in glioblastoma is primarily explained by tumor infiltration with AQP9 expressing leukocytes. Immunolabeling confirmed that within tumor regions, AQP9 was expressed in CD15(+) and Calgranulin B+ leukocytes, but also in larger cells that morphologically resembled glioma cells. Specificity of immunoreagents was tested in recombinant cell lines, leukocyte preparations, and sections of normal human brain and liver tissue. Apparent AQP9(+) glioma cells were frequently observed in proximity to blood vessels, where brain tumor stem cells have been observed previously. A fraction of these larger AQP9 expressing cells co-expressed the differentiated astrocyte marker GFAP. AQP9 expressing glioma cells were negative for the brain tumor stem cell marker CD15, but were observed in proximity to CD15(+) glioma cells. AQP9 expression may therefore require signals of the perivascular tumor environment or alternatively it may be restricted to a population of glioma stem cell early progenitor cells.
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| 2. |
- Liu Carlsen, Anting, et al.
(author)
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Circulating MicroRNA Expression Profiles Associated With Systemic Lupus Erythematosus
- 2013
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In: Arthritis and Rheumatism. - : Wiley-Blackwell. - 0004-3591 .- 1529-0131. ; 65:5, s. 1324-1334
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Journal article (peer-reviewed)abstract
- Objective To evaluate the specificity of expression patterns of cell-free circulating microRNAs (miRNAs) in systemic lupus erythematosus (SLE). Methods Total RNA was purified from plasma, and 45 different specific, mature miRNAs were determined using quantitative reverse transcriptionpolymerase chain reaction assays. A total of 409 plasma samples were obtained from 364 different patients with SLE, healthy control subjects, and control subjects with other autoimmune diseases. The results in the primary cohort of 62 patients with SLE and 29 healthy control subjects were validated in 2 independent cohorts: a validation cohort comprising 68 patients with SLE and 68 healthy control subjects, and a disease control cohort comprising 20 patients with SLE (19 of whom were from the other validation cohort), 46 healthy control subjects, 38 patients with vasculitis, 18 patients with rheumatoid arthritis, and 20 immunosuppressed patients. Results Seven miRNAs were statistically significantly differentially expressed in plasma from patients with SLE. The expression of miRNA-142-3p (miR-142-3p) and miR-181a was increased, and the expression of miR-106a, miR-17, miR-20a, miR-203, and miR-92a was decreased. In addition, the expression of miR-342-3p, miR-223, and miR-20a was significantly decreased in SLE patients with active nephritis. A predictive model for SLE based on 2 or 4 miRNAs differentiated patients with SLE from control subjects (76% accuracy) when validated independently (P andlt; 2 x 109). Use of the 4-miRNA model provided highly significant differentiation between the SLE group and disease controls, except for those with vasculitis. Conclusion Circulating miRNAs are systematically altered in SLE. A 4-miRNA signature was diagnostic of SLE, and a specific subset of miRNA profiles was associated with nephritis. All of the signature miRNAs target genes in the transforming growth factor signaling pathways. Other targets include regulation of apoptosis, cytokinecytokine receptors, T cell development, and cytoskeletal organization. These findings highlight possible dysregulated pathways in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes.
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| 3. |
- Nielsen, Niklas, et al.
(author)
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Targeted Temperature Management at 33 degrees C versus 36 degrees C after Cardiac Arrest
- 2013
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In: New England Journal of Medicine. - 0028-4793. ; 369:23, s. 2197-2206
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Journal article (peer-reviewed)abstract
- BackgroundUnconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. MethodsIn an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33 degrees C or 36 degrees C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. ResultsIn total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33 degrees C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36 degrees C group (225 of 466 patients) (hazard ratio with a temperature of 33 degrees C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33 degrees C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36 degrees C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. ConclusionsIn unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33 degrees C did not confer a benefit as compared with a targeted temperature of 36 degrees C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.)
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| 4. |
- Orlando, Ludovic, et al.
(author)
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Recalibrating Equus evolution using the genome sequence of an early Middle Pleistocene horse
- 2013
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 499:7456, s. 74-
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Journal article (peer-reviewed)abstract
- The rich fossil record of equids has made them a model for evolutionary processes(1). Here we present a 1.12-times coverage draft genome from a horse bone recovered from permafrost dated to approximately 560-780 thousand years before present (kyr BP)(2,3). Our data represent the oldest full genome sequence determined so far by almost an order of magnitude. For comparison, we sequenced the genome of a Late Pleistocene horse (43 kyr BP), and modern genomes of five domestic horse breeds (Equus ferus caballus), a Przewalski's horse (E. f. prze-walskii) and a donkey (E. asinus). Our analyses suggest that the Equus lineage giving rise to all contemporary horses, zebras and donkeys originated 4.0-4.5 million years before present (Myr BP), twice the conventionally accepted time to the most recent common ancestor of the genus Equus(4,5). We also find that horse population size fluctuated multiple times over the past 2 Myr, particularly during periods of severe climatic changes. We estimate that the Przewalski's and domestic horse populations diverged 38-72 kyr BP, and find no evidence of recent admixture between the domestic horse breeds and the Przewalski's horse investigated. This supports the contention that Przewalski's horses represent the last surviving wild horse population(6). We find similar levels of genetic variation among Przewalski's and domestic populations, indicating that the former are genetically viable and worthy of conservation efforts. We also find evidence for continuous selection on the immune system and olfaction throughout horse evolution. Finally, we identify 29 genomic regions among horse breeds that deviate from neutrality and show low levels of genetic variation compared to the Przewalski's horse. Such regions could correspond to loci selected early during domestication.
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| 5. |
- Wacker, Soeren J., et al.
(author)
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The identification of novel, high affinity AQP9 inhibitors in an intracellular binding site
- 2013
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In: Molecular Membrane Biology. - : Informa UK Limited. - 0968-7688 .- 1464-5203. ; 30:3, s. 246-260
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Journal article (peer-reviewed)abstract
- Background: The involvement of aquaporin (AQP) water and small solute channels in the etiology of several diseases, including cancer, neuromyelitis optica and body fluid imbalance disorders, has been suggested previously. Furthermore, results obtained in a mouse model suggested that AQP9 function contributes to hyperglycemia in type-2 diabetes. In addition, the physiological role of several AQP family members remains poorly understood. Small molecule inhibitors of AQPs are therefore desirable to further study AQP physiological and pathophysiological functions. Methods: The binding of recently established AQP9 inhibitors to a homology model of AQP9 was investigated by molecular dynamics simulations and molecular docking. Putative inhibitor binding sites identified with this procedure were modified by site-directed mutagenesis. Active compounds were measured in a mammalian cell water permeability assay of mutated AQP9 isoforms and tested for changes in inhibitory effects. Controls: Three independent cell lines were established for each mutated AQP9 isoform and functionality of mutant isoforms was established. Principal findings: We have identified putative binding sites of recently established AQP9 inhibitors. This information facilitated successful identification of novel AQP9 inhibitors with low micromolar IC50 values in a cell based assay by in silico screening of a compound library targeting specifically this binding site. Significance: We have established a successful strategy for AQP small molecule inhibitor identification. AQP inhibitors may be relevant as experimental tools, to enhance our understanding of AQP function, and in the treatment of various diseases.
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