| 1. |
- Holmfeldt, Linda, et al.
(författare)
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The genomic landscape of hypodiploid acute lymphoblastic leukemia
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:3, s. 242-252
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Tidskriftsartikel (refereegranskat)abstract
- The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.
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| 2. |
- Hannan, Johanna L., et al.
(författare)
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Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats
- 2014
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Ingår i: Journal of Sexual Medicine. - : Wiley-Blackwell. - 1743-6095 .- 1743-6109. ; 11:6, s. 1442-1451
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Bilateral cavernous nerve injury (BCNI) causes profound penile changes such as apoptosis and fibrosis leading to erectile dysfunction (ED). Histone deacetylase (HDAC) has been implicated in chronic fibrotic diseases. Aims This study will characterize the molecular changes in penile HDAC after BCNI and determine if HDAC inhibition can prevent BCNI-induced ED and penile fibrosis. Methods Five groups of rats (8-10 weeks, n=10/group) were utilized: (i) sham; (ii and iii) BCNI 14 and 30 days following injury; and (iv and v) BCNI treated with HDAC inhibitor valproic acid (VPA 250mg/kg; 14 and 30 days). All groups underwent cavernous nerve stimulation (CNS) to determine intracavernosal pressure (ICP). Penile HDAC3, HDAC4, fibronectin, and transforming growth factor-1 (TGF-1) protein expression (Western blot) were assessed. Trichrome staining and the fractional area of fibrosis were determined in penes from each group. Cavernous smooth muscle content was assessed by immunofluorescence to alpha smooth muscle actin (-SMA) antibodies. Main Outcome Measures We measured ICP; HDAC3, HDAC4, fibronectin, and TGF-1 protein expression; penile fibrosis; penile -SMA content. Results There was a voltage-dependent decline (Pless than0.05) in ICP to CNS 14 and 30 days after BCNI. Penile HDAC3, HDAC4, and fibronectin were significantly increased (Pless than0.05) 14 days after BCNI. There was a slight increase in TGF-1 protein expression after BCNI. Histological analysis showed increased (Pless than0.05) corporal fibrosis after BCNI at both time points. VPA treatment decreased (Pless than0.05) penile HDAC3, HDAC4, and fibronectin protein expression as well as corporal fibrosis. There was no change in penile -SMA between all groups. Furthermore, VPA-treated BCNI rats had improved erectile responses to CNS (Pless than0.05). Conclusion HDAC-induced pathological signaling in response to BCNI contributes to penile vascular dysfunction. Pharmacological inhibition of HDAC prevents penile fibrosis, normalizes fibronectin expression, and preserves erectile function. The HDAC pathway may represent a suitable target in preventing the progression of ED occurring post-radical prostatectomy.
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| 3. |
- Hannan, Johanna L., et al.
(författare)
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Inhibition of Rho-Kinase Improves Erectile Function, Increases Nitric Oxide Signaling and Decreases Penile Apoptosis in a Rat Model of Cavernous Nerve Injury
- 2013
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Ingår i: Journal of Urology. - : Elsevier. - 0022-5347 .- 1527-3792. ; 189:3, s. 1155-1161
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Bilateral cavernous nerve injury results in up-regulation of ROCK signaling in the penis. This is linked to erectile dysfunction in an animal model of post-prostatectomy erectile dysfunction. We evaluated whether daily treatment with the ROCK inhibitor Y-27632 (Tocris Bioscience, Ellisville, Missouri) would prevent erectile dysfunction in a rat model of bilateral cavernous nerve injury.Materials and Methods: Sprague-Dawley(R) rats underwent surgery to create sham (14) or bilateral (27) cavernous nerve injury. In the injury group 13 rats received treatment with Y-27632 (5 mg/kg twice daily) and 14 received vehicle. At 14 days after injury, rats underwent cavernous nerve stimulation to determine erectile function. Penes were assessed for neuronal and nitric oxide synthase membrane-endothelial nitric oxide synthase. ROCK2 was assessed by Western blot. Cyclic guanosine monophosphate was determined by enzyme-linked immunosorbent assay. Cavernous homogenates were tested for ROCK and protein kinase G enzymatic activity. Penile apoptosis was evaluated using the Apostain technique (Alexis, San Diego, California). Data were analyzed on ROCK using ANOVA and the t test.Results: While erectile function was decreased in rats with bilateral cavernous nerve injury, daily administration of Y-27632 improved erectile responses. Injury decreased neuronal and nitric oxide synthase membrane-endothelial nitric oxide synthase but ROCK2 was significantly increased. Y-27632 treatment restored neuronal nitric oxide synthase, nitric oxide synthase membrane-endothelial nitric oxide synthase and cyclic guanosine monophosphate levels, and protein kinase G activity. Treatment significantly decreased ROCK2 protein and ROCK activity. There were significantly fewer apoptotic cells after treatment than in injured controls.Conclusions: These results provide evidence for up-regulation of the RhoA/ROCK signaling pathway with detrimental effects on erectile function after bilateral cavernous nerve injury. ROCK inhibition improved erectile dysfunction associated with bilateral cavernous nerve injury by preserving penile nitric oxide bioavailability and decreasing penile apoptosis.
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| 6. |
- Setälä, H., et al.
(författare)
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Urban and agricultural soils : Conflicts and trade-offs in the optimization of ecosystem services
- 2014
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Ingår i: Urban Ecosystems. - : Springer Science and Business Media LLC. - 1083-8155 .- 1573-1642. ; 17:1, s. 239-253
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Tidskriftsartikel (refereegranskat)abstract
- On-going human population growth and changing patterns of resource consumption are increasing global demand for ecosystem services, many of which are provided by soils. Some of these ecosystem services are linearly related to the surface area of pervious soil, whereas others show non-linear relationships, making ecosystem service optimization a complex task. As limited land availability creates conflicting demands among various types of land use, a central challenge is how to weigh these conflicting interests and how to achieve the best solutions possible from a perspective of sustainable societal development. These conflicting interests become most apparent in soils that are the most heavily used by humans for specific purposes: urban soils used for green spaces, housing, and other infrastructure and agricultural soils for producing food, fibres and biofuels. We argue that, despite their seemingly divergent uses of land, agricultural and urban soils share common features with regards to interactions between ecosystem services, and that the trade-offs associated with decision-making, while scale- and context-dependent, can be surprisingly similar between the two systems. We propose that the trade-offs within land use types and their soil-related ecosystems services are often disproportional, and quantifying these will enable ecologists and soil scientists to help policy makers optimizing management decisions when confronted with demands for multiple services under limited land availability.
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| 7. |
- Ameur, Adam, et al.
(författare)
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Comprehensive profiling of the vaginal microbiome in HIV positive women using massive parallel semiconductor sequencing
- 2014
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 4, s. 4398-
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Tidskriftsartikel (refereegranskat)abstract
- Infections by HIV increase the risk of acquiring secondary viral and bacterial infections and methods are needed to determine the spectrum of co-infections for proper treatment. We used rolling circle amplification (RCA) and Ion Proton sequencing to investigate the vaginal microbiome of 20 HIV positive women from South Africa. A total of 46 different human papillomavirus (HPV) types were found, many of which are not detected by existing genotyping assays. Moreover, the complete genomes of two novel HPV types were determined. Abundance of HPV infections was highly correlated with real-time PCR estimates, indicating that the RCA-Proton method can be used for quantification of individual pathogens. We also identified a large number of other viral, bacterial and parasitic co-infections and the spectrum of these co-infections varied widely between individuals. Our method provides rapid detection of a broad range of pathogens and the ability to reconstruct complete genomes of novel infectious agents.
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| 8. |
- Bartels, Ronald H M A, et al.
(författare)
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External validation of a model to predict the survival of patients presenting with a spinal epidural metastasis.
- 2011
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Ingår i: Cancer metastasis reviews. - : Springer Science and Business Media LLC. - 1573-7233 .- 0167-7659. ; 30:2, s. 153-9
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Tidskriftsartikel (refereegranskat)abstract
- The surgical treatment of spinal metastases is evolving. The major problem is the selection of patients who may benefit from surgical treatment. One of the criteria is an expected survival of at least 3 months. A prediction model has been previously developed. The present study has been performed in order to validate externally the model and to demonstrate that this model can be generalized to other institutions and other countries than the Netherlands. Data of 356 patients from five centers in Germany, Spain, Sweden, and the Netherlands who were treated for metastatic epidural spinal cord compression were collected. Hazard ratios in the test population corresponded with those of the developmental population. However, the observed and the expected survival were different. Analysis revealed that the baseline hazard function was significantly different. This tempted us to combine the data and develop a new prediction model. Estimating iteratively, a baseline hazard was composed. An adapted prediction model is presented. External validation of a prediction model revealed a difference in expected survival, although the relative contribution of the specific hazard ratios was the same as in the developmental population. This study emphasized the need to check the baseline hazard function in external validation. A new model has been developed using an estimated baseline hazard.
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| 9. |
- Breure, AM, et al.
(författare)
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Ecosystem services: a useful concept for soil policy making!
- 2012
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Ingår i: Current Opinion in Environmental Sustainability. - : Elsevier BV. - 1877-3443 .- 1877-3435. ; 4:5, s. 578-585
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Forskningsöversikt (refereegranskat)abstract
- This paper is based on the session ‘Ecosystem services: a useful concept for soil policy making?’ at the Wageningen Applied Soil Conference in September 2011. In that session it was shown from different angles that policy awareness of the dependence of humankind on ecosystem services has resulted in the development of tools for optimal allocation and quantification of ecosystem services and raising awareness to stakeholders and decision makers. A number of case studies provided practical applications of developed tools that show how an ecosystem services approach can work as a way to value ecosystems. The use of ecosystem services may lead to mitigation of soil degradation and at the same time increase production of services both to private land owners as well as to the society as common goods. In our opinion the results available to date show that quantifying the benefits of ecosystems is a way to support the positive view stated in the title and we encourage the development of decision support tools based on more extensive yet user friendly integrated approaches of resource management, sector planning, and priority setting in the near future.
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| 10. |
- Deng, QL, et al.
(författare)
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Specific and integrated roles of Lmx1a, Lmx1b and Phox2a in ventral midbrain development
- 2011
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Ingår i: Development (Cambridge, England). - : The Company of Biologists. - 1477-9129 .- 0950-1991. ; 138:16, s. 3399-3408
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Tidskriftsartikel (refereegranskat)abstract
- The severe disorders associated with a loss or dysfunction of midbrain dopamine neurons (DNs) have intensified research aimed at deciphering developmental programs controlling midbrain development. The homeodomain proteins Lmx1a and Lmx1b are important for the specification of DNs during embryogenesis, but it is unclear to what degree they may mediate redundant or specific functions. Here, we provide evidence showing that DN progenitors in the ventral midbrain can be subdivided into molecularly distinct medial and lateral domains, and these subgroups show different sensitivity to the loss of Lmx1a and Lmx1b. Lmx1a is specifically required for converting non-neuronal floor-plate cells into neuronal DN progenitors, a process that involves the establishment of Notch signaling in ventral midline cells. On the other hand, lateral DN progenitors that do not appear to originate from the floor plate are selectively ablated in Lmx1b mutants. In addition, we also reveal an unanticipated role for Lmx1b in regulating Phox2a expression and the sequential specification of ocular motor neurons (OMNs) and red nucleus neurons (RNNs) from progenitors located lateral to DNs in the midbrain. Our data therefore establish that Lmx1b influences the differentiation of multiple neuronal subtypes in the ventral midbrain, whereas Lmx1a appears to be exclusively devoted to the differentiation of the DN lineage.
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