| 1. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 2. |
- Giuliani, G., et al.
(författare)
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Round-Robin Measurements of Linewidth Enhancement Factor of Semiconductor Lasers in COST 288 Action
- 2007
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Ingår i: Lasers and Electro-Optics, 2007 and the International Quantum Electronics Conference. CLEOE-IQEC 2007. European Conference on. - 1424409306 - 9781424409303 ; , s. 4385967-
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Konferensbidrag (refereegranskat)abstract
- Round-robin measurements on the linewidth enhancement factor are carried out in many laboratories participating to EU COST 288 Action. Up to 7 different techniques are applied to DFB, VCSELs, QCL, and QD lasers, and results are compared.
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| 3. |
- Bergman, Lina, 1982, et al.
(författare)
-
Preeclampsia and increased permeability over the blood brain barrier - a role of vascular endothelial growth receptor 2.
- 2021
-
Ingår i: American journal of hypertension. - : Oxford University Press (OUP). - 1941-7225 .- 0895-7061. ; 34:1, s. 73-81
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral complications in preeclampsia are leading causes of maternal mortality worldwide but the underlying pathophysiology is largely unknown and a challenge to study. Using an in vitro model of the human blood brain barrier (BBB), we explored the role of vascular endothelial growth factor receptor 2 (VEGFR2) in preeclampsia.The human brain endothelial cell line (hCMEC/D3) cultured on Tranwells insert were exposed (12h) to plasma from women with preeclampsia (n=28), normal pregnancy (n=28) and non-pregnant (n=16) controls. Transendothelial electrical resistance (TEER) and permeability to 70kDa FITC-dextran were measured for assessment of BBB integrity. We explored possible underlying mechanisms, with focus on expression of tight junction proteins and phosphorylation of two tyrosine residues of VEGFR2, associated with vascular permeability and migration (pY951) and cell proliferation (pY1175). Plasma concentrations of soluble FMS like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured in order to establish correlations with in vitro results.hCMEC/D3 exposed to plasma from women with preeclampsia exhibited reduced TEER and increased permeability to 70kDa FITC-dextran. Further, these cells up-regulated the mRNA levels of VEGFR2, as well as pY951-VEGFR2; but reduced pY1175-VEGFR2 (p&0.05 in all cases). No difference in mRNA expression of tight junction protein was observed between gruops. There was no correlation between angiogenic biomarkers and BBB permeability.We present a promising in vitro model of the BBB in preeclampsia. Selective tyrosine phosphorylation of VEGFR2 may participate in the increased BBB permeability in preeclampsia irrespective of plasma concentrations of angiogenic biomarkers.
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| 4. |
- Johansson, Patrik, et al.
(författare)
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A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma
- 2020
-
Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 32:2
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells, We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.
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| 5. |
- Kaffes, Ioannis, et al.
(författare)
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Human Mesenchymal glioblastomas are characterized by an increased immune cell presence compared to Proneural and Classical tumors
- 2019
-
Ingår i: Oncoimmunology. - : TAYLOR & FRANCIS INC. - 2162-4011 .- 2162-402X. ; 8:11
-
Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults, with a median survival of 14.6 months. Recent efforts have focused on identifying clinically relevant subgroups to improve our understanding of pathogenetic mechanisms and patient stratification. Concurrently, the role of immune cells in the tumor microenvironment has received increasing attention, especially T cells and tumor-associated macrophages (TAM). The latter are a mixed population of activated brain-resident microglia and infiltrating monocytes/monocyte-derived macrophages, both of which express ionized calcium-binding adapter molecule 1 (IBA1). This study investigated differences in immune cell subpopulations among distinct transcriptional subtypes of GBM. Human GBM samples were molecularly characterized and assigned to Proneural, Mesenchymal or Classical subtypes as defined by NanoString nCounter Technology. Subsequently, we performed and analyzed automated immunohistochemical stainings for TAM as well as specific T cell populations. The Mesenchymal subtype of GBM showed the highest presence of TAM, CD8(+), CD3(+) and FOXP3(+) T cells, as compared to Proneural and Classical subtypes. High expression levels of the TAM-related gene AIF1, which encodes the TAM-specific protein IBA1, correlated with a worse prognosis in Proneural GBM, but conferred a survival benefit in Mesenchymal tumors. We used our data to construct a mathematical model that could reliably identify Mesenchymal GBM with high sensitivity using a combination of the aforementioned cell-specific IHC markers. In conclusion, we demonstrated that molecularly distinct GBM subtypes are characterized by profound differences in the composition of their immune microenvironment, which could potentially help to identify tumors amenable to immunotherapy.
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| 6. |
- Nelander, Rikard, et al.
(författare)
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Fingerprints of spatial charge transfer in Quantum Cascade Lasers
- 2007
-
Ingår i: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 102, s. 1-113104
-
Tidskriftsartikel (refereegranskat)abstract
- We show that mid-infrared transmission spectroscopy of a quantum cascade laser provides clear-cut information on changes in charge location at different bias. Theoretical simulations of the evolution of the gain/absorption spectrum for a lambda~7.4 µm InGaAs/AlInAs/InP quantum cascade laser have been compared with the experimental findings. Transfer of electrons between the ground states in the active region and the states in the injector goes hand in hand with a decrease of discrete intersubband absorption peaks and an increase of broad, high-energy absorption toward the continuum delocalized states above the barriers.
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| 7. |
- Pereira, M. F., Jr., et al.
(författare)
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Characterization of intersubband devices combining a nonequilibrium many body theory with transmission spectroscopy experiments
- 2007
-
Ingår i: Journal of Materials Science: Materials in Electronics. - : Springer Science and Business Media LLC. - 0957-4522 .- 1573-482X. ; 18:7, s. 689-694
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Tidskriftsartikel (refereegranskat)abstract
- In this paper we apply a microscopic nonequilibrium many body Keldysh Green's functions approach to an analysis of complex intersubband optical materials and devices. The calculated absorption/gain spectra are in very good agreement with transmission spectroscopy measurements of quantum cascade laser structures operating in the mid-infrared (midIR). The very good agreement reached between theoretical results and experimental measurements benchmarks the predictive power of our algorithms and its potential as a design tool for efficient intersubband designs.
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| 8. |
- Revin, D.G., et al.
(författare)
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Probing the electronic and optical properties of quantum cascade lasers under operating conditions
- 2006
-
Ingår i: Proceedings of SPIE, the International Society for Optical Engineering. - : SPIE. ; 6386, s. 1-63860
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- We report the realisation of spectroscopic broadband transmission experiments on quantum cascade lasers (QCLs) under continuous wave operating conditions for drive currents up to laser threshold. This technique allows, for the first time, spectroscopic study of light transmission through the waveguide of QCLs in a very broad spectral range (λ~1.5-12 μm), limited only by the detector response and by interband absorption in the materials used in the QCL cladding regions. Waveguide transmittance spectra have been studied for both TE and TM polarization, for InGaAs/InAlAs/InP QCLs with different active region designs emitting at 7.4 and 10μm. The transmission measurements clearly show the depopulation of the lower laser levels as bias is increased, the onset and growth of optical amplification at the energy corresponding to the laser transitions as current is increased towards threshold, and the thermal filling of the second laser level and decrease of material gain at high temperatures. This technique also allows direct determination of key parameters such as the exact temperature of the laser core region under operating conditions, as well as the modal gain and waveguide loss coefficients.
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| 9. |
- Andersen, J., et al.
(författare)
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Competition between weak OH·π and CH·O hydrogen bonds : THz spectroscopy of the C2H2 - H2O and C2H4 - H2O complexes
- 2017
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 146:19
-
Tidskriftsartikel (refereegranskat)abstract
- THz absorption spectra have been recorded for the weakly bound molecular complexes of H2O with C2H4 and C2H2 embedded in cryogenic neon matrices at 2.8 K. The observation and assignment of a large-amplitude acceptor OH librational mode of the C2H2 - H2O complex at 145.5 cm−1 confirms an intermolecular CH⋯O hydrogen-bonded configuration of C2v symmetry with the H2O subunit acting as the hydrogen bond acceptor. The observation and assignment of two large-amplitude donor OH librational modes of the C2H4 - H2O complex at 255.0 and 187.5 cm−1, respectively, confirms an intermolecular OH⋯π hydrogen-bonded configuration with the H2O subunit acting as the hydrogen bond donor to the π-cloud of C2H4. A (semi)-empirical value for the change of vibrational zero-point energy of 4.0-4.1 kJ mol−1 is proposed and the combination with quantum chemical calculations at the CCSD(T)-F12b/aug-cc-pVQZ level provides a reliable estimate of 7.1 ± 0.3 kJ mol−1 for the dissociation energy D0 of the C2H4 - H2O complex. In addition, tentative assignments for the two strongly infrared active OH librational modes of the ternary C2H4 - HOH - C2H4 complex having H2O as a doubly OH·π hydrogen bond donor are proposed at 213.6 and 222.3 cm−1. The present findings demonstrate that the relative stability of the weak hydrogen bond motifs is not entirely rooted in differences of electronic energy but also to a large extent by differences in the vibrational zero-point energy contributions arising from the class of large-amplitude intermolecular modes.
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| 10. |
- Andersen, J., et al.
(författare)
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Far-Infrared Investigation of the Benzene-Water Complex : The Identification of Large-Amplitude Motion and Tunneling Pathways
- 2020
-
Ingår i: Journal of Physical Chemistry A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 124:3, s. 513-519
-
Tidskriftsartikel (refereegranskat)abstract
- The far-infrared spectrum of the weakly OH···πhydrogen-bonded benzene-water complex has been studied in neon and argon matrices, below 30 K. The in-plane water libration has been observed in both neon and argon for H2O and D2O complexed with C6H6 and C6D6 but not for the corresponding complexes involving HDO. Both H2O and D2O can tunnel between the two possible hydrogen bonds. This is not possible for HDO. The reported far-infrared observations have implications for the interpretation of the previously obtained molecular beam microwave spectrum of the benzene-water complex.
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| 11. |
- Barretina, Jordi, et al.
(författare)
-
Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.
- 2010
-
Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:8, s. 715-21
-
Tidskriftsartikel (refereegranskat)abstract
- Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.
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| 12. |
- Cvijovic, Marija, 1977, et al.
(författare)
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Bridging the gaps in systems biology
- 2014
-
Ingår i: Molecular Genetics and Genomics. - : Springer Science and Business Media LLC. - 1617-4615 .- 1617-4623. ; 289:5, s. 727-734
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Tidskriftsartikel (refereegranskat)abstract
- Systems biology aims at creating mathematical models, i.e., computational reconstructions of biological systems and processes that will result in a new level of understanding-the elucidation of the basic and presumably conserved "design" and "engineering" principles of biomolecular systems. Thus, systems biology will move biology from a phenomenological to a predictive science. Mathematical modeling of biological networks and processes has already greatly improved our understanding of many cellular processes. However, given the massive amount of qualitative and quantitative data currently produced and number of burning questions in health care and biotechnology needed to be solved is still in its early phases. The field requires novel approaches for abstraction, for modeling bioprocesses that follow different biochemical and biophysical rules, and for combining different modules into larger models that still allow realistic simulation with the computational power available today. We have identified and discussed currently most prominent problems in systems biology: (1) how to bridge different scales of modeling abstraction, (2) how to bridge the gap between topological and mechanistic modeling, and (3) how to bridge the wet and dry laboratory gap. The future success of systems biology largely depends on bridging the recognized gaps.
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| 13. |
- Heydarkhan-Hagvall, Sepideh, 1969, et al.
(författare)
-
DNA microarray study on gene expression profiles in co-cultured endothelial and smooth muscle cells in response to 4- and 24-h shear stress
- 2006
-
Ingår i: Molecular and cellular biochemistry. - : Springer Science and Business Media LLC. - 0300-8177 .- 1573-4919. ; 281:1-2, s. 1-15
-
Tidskriftsartikel (refereegranskat)abstract
- Shear stress, a major hemodynamic force acting on the vessel wall, plays an important role in physiological processes such as cell growth, differentiation, remodelling, metabolism, morphology, and gene expression. We investigated the effect of shear stress on gene expression profiles in co-cultured vascular endothelial cells (ECs) and smooth muscle cells (SMCs). Human aortic ECs were cultured as a confluent monolayer on top of confluent human aortic SMCs, and the EC side of the co-culture was exposed to a laminar shear stress of 12 dyn/cm(2) for 4 or 24 h. After shearing, the ECs and SMCs were separated and RNA was extracted from the cells. The RNA samples were labelled and hybridized with cDNA array slides that contained 8694 genes. Statistical analysis showed that shear stress caused the differential expression (p < or = 0.05) of a total of 1151 genes in ECs and SMCs. In the co-cultured ECs, shear stress caused the up-regulation of 403 genes and down-regulation of 470. In the co-cultured SMCs, shear stress caused the up-regulation of 152 genes and down-regulation of 126 genes. These results provide new information on the gene expression profile and its potential functional consequences in co-cultured ECs and SMCs exposed to a physiological level of laminar shear stress. Although the effects of shear stress on gene expression in monocultured and co-cultured EC are generally similar, the response of some genes to shear stress is opposite between these two types of culture (e.g., ICAM-1 is up-regulated in monoculture and down-regulated in co-culture), which strongly indicates that EC-SMC interactions affect EC responses to shear stress.
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| 14. |
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| 15. |
- Andersen, J, et al.
(författare)
-
Communication: THz absorption spectrum of the CO2-H2O complex: Observation and assignment of intermolecular van der Waals vibrations.
- 2014
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 140:9
-
Tidskriftsartikel (refereegranskat)abstract
- Terahertz absorption spectra have been recorded for the weakly bound CO2-H2O complex embedded in cryogenic neon matrices at 2.8 K. The three high-frequency van der Waals vibrational transitions associated with out-of-plane wagging, in-plane rocking, and torsional motion of the isotopic H2O subunit have been assigned and provide crucial observables for benchmark theoretical descriptions of this systems' flat intermolecular potential energy surface. A (semi)-empirical value for the zero-point energy of 273 ± 15 cm(-1) from the class of intermolecular van der Waals vibrations is proposed and the combination with high-level quantum chemical calculations provides a value of 726 ± 15 cm(-1) for the dissociation energy D0.
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| 16. |
- Ceponkus, J, et al.
(författare)
-
A simple model for the water o-H-2 complex
- 2006
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 124:2
-
Tidskriftsartikel (refereegranskat)abstract
- The infrared spectrum of the complex between o-H-2 and H2O, D2O, or HDO, isolated in a matrix of solid p-H-2, has been studied between 20 and 4500 cm(-1). In addition the infrared spectrum of the complex between p-D-2 and H2O in solid o-D-2 has been studied. The spectral shifts are interpreted as the result of the quadrupole-dipole interaction between hydrogen and water. (c) 2006 American Institute of Physics.
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| 17. |
- Ceponkus, J, et al.
(författare)
-
Acceptor switching and axial rotation of the water dimer in matrices, observed by infrared spectroscopy.
- 2010
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 133:7
-
Tidskriftsartikel (refereegranskat)abstract
- Several isotopologues of the water dimer have been studied in different matrices (Ne, Ar, Kr, and p-H(2)) at very low temperatures. A fine structure, which is more or less matrix independent and very similar for different intramolecular fundamentals of the same isotopologic dimer, is present on the high wavenumber side of the main component. The bound OD (OH) stretches of the donor have temperature dependent components. The fine structure and temperature dependency is interpreted as evidence for acceptor switching and rotation of the water dimer around its O-O axis in the matrices studied here. The slow nuclear spin equilibration in H(2)O inhibits the thermal equilibration between the acceptor switching states in H(2)O-DOH and H(2)O-DOD. The condensed environment slows down the acceptor switching rate compared to the gas phase. The antisymmetric stretch of the proton acceptor is assigned by combining information from different matrices with the rotation-acceptor switching model.
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| 18. |
- Ceponkus, J, et al.
(författare)
-
Complex Formation of Small Molecules during Isolation in Low Temperature Matrices: Water Dimers in p-H-2 and Ne Matrices
- 2010
-
Ingår i: The Journal of Physical Chemistry Part A: Molecules, Spectroscopy, Kinetics, Environment and General Theory. - : American Chemical Society (ACS). - 1520-5215. ; 114:25, s. 6829-6831
-
Tidskriftsartikel (refereegranskat)abstract
- The concentrations of water dimer are compared in Ne and p-H-2 matrices at low temperatures, using infrared spectroscopy. Additional data are given for o-D-2 and Ar matrices. For a given monomer concentration, the dimer concentration is significantly higher in solid Ne (or Ar) than in solid p-H-2. In p-H-2, the dimer concentration is only slightly higher than expected for a random distribution of water in the matrix. The dimer concentration in o-D-2 matrices is intermediate between p-H-2 and noble gas matrices. This strongly suggests that most dimers form on the surface of the growing matrix, and not as the result of diffusion in the bulk of the matrix.
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| 19. |
- Ceponkus, J, et al.
(författare)
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Intermolecular vibrations of different isotopologs of the water dimer: Experiments and density functional theory calculations.
- 2008
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 129:19
-
Tidskriftsartikel (refereegranskat)abstract
- Far infrared spectra of seven different isotopologs of the water dimer have been measured in neon matrices at 2.8 K. The experiments are interpreted with the aid of density functional theory calculations, in particular the calculated harmonic isotopic shifts were utilized. All six intermolecular vibrational modes of the water dimer and the fully deuterated water dimer are assigned based the isotopic shifts induced. 31 of a total of 42 intermolecular fundamental modes of the seven different H, D, and (18)O containing water dimers have been experimentally observed and assigned accordingly. The overall agreement between the calculations and the experiments of all isotopologs results in a complete and consistent description of these modes.
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| 20. |
- Ceponkus, J, et al.
(författare)
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Observations of Host Guest Interactions Specific to Molecular Matrices: Water Monomers and Dimers in Hydrogen Matrices.
- 2011
-
Ingår i: Journal of physical chemistry. A. - : American Chemical Society (ACS). - 1520-5215 .- 1089-5639. ; 115:27, s. 7921-7927
-
Tidskriftsartikel (refereegranskat)abstract
- Water monomers and dimers have been studied at low temperatures in matrices of solid p-H(2), o-D(2), n-H(2), and n-D(2) using infrared spectroscopy. Our data demonstrate interaction mechanisms between host matrix and guest molecules that are different from the ones observed in atomic noble gas matrices. Notably both guest/host rotational-rotational interaction and matrix induced modifications of the guest libration modes are observed. We also show that different types of interaction influence the relaxation times of some of guest modes. Water rotates freely in p-H(2) and o-D(2) but librates in n-H(2) and n-D(2). Rotational relaxation is faster in o-D(2) than in p-H(2) and faster in p-H(2) than in Ne. This is attributed to interactions between water rotation and matrix molecule rotation in p-H(2) and o-D(2). In n-H(2) and n-D(2), a strong water libration band is observed in the far-infrared, and strong water monomer vibration bands have libration satellites. Water dimer bands, close to matrix rotation bands, are perturbed by the matrix motions. The H-bonded isomer H(2)O-HOD rapidly converts to the D-bonded form H(2)O-DOH in p-H(2) and in o-D(2) but slowly in n-H(2) and n-D(2).
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| 21. |
- Ceponkus, J, et al.
(författare)
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On the structure of the matrix isolated water trimer.
- 2011
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 134:6
-
Tidskriftsartikel (refereegranskat)abstract
- Infrared spectra of partially deuterated water trimers have been investigated. It is found that HDO(H(2)O)(2) has a single, bound OD stretching fundamental, (HDO)(2)H(2)O two bound OD stretches. (HDO)(3) has a single, bound OD stretch and (H(2)O)(3) has a pair of bound OH stretches. Ab initio and discrete Fourier transform (DFT) calculations predict that the water trimer has C(1) symmetry with six different, isoenergetic minima. These calculations consequently give three numerically different OD stretches for HDO(H(2)O)(2), six for (HDO)(2)H(2)O, three for (HDO)(3), and three bound OH stretches for (H(2)O)(3). The connection between the observations and the pseudorotation of the trimer is discussed with the help of Wales' pseudorotation model. It is found that pseudorotation is sufficiently fast to average the effective symmetry of the A(3) trimer to C(3h) and to eliminate the difference between the different ab initio minima for A(2)B. The only exception is (H(2)O)(3) where the splitting between the different bound OH stretches is largest. Here a doublet is observed due to incomplete averaging. DFT calculations indicate that the D-bonded form of HDO(H(2)O)(2) is between 50 and 60 cm(-1) more stable than the H-bonded form. The energy difference is determined by differences in zero point vibration energy of intermolecular librations of the two forms. Attempts to measure the energy difference indicate that the energy difference is larger, of the order of 100 cm(-1).
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| 22. |
- Ceponkus, J, et al.
(författare)
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Rotation of Water in Solid Parahydrogen and Orthodeuterium.
- 2010
-
Ingår i: Journal of physical chemistry. A. - : American Chemical Society (ACS). - 1520-5215 .- 1089-5639. ; 114, s. 12979-12985
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Tidskriftsartikel (refereegranskat)abstract
- The far-infrared spectra of solid orthodeuterium and solid normal deuterium are presented and compared to the corresponding spectra of solid parahydrogen and solid normal hydrogen. Spectra of water in orthodeuterium are compared to spectra of water in parahydrogen. The water rotation constants in orthodeuterium are approximately 80% of the rotation constants of water in parahydrogen. The S(0)(0) band of orthodeuterium gets a strong satellite in the presence of water. The position and width of the satellite depends on the isotopic composition of the water present. If there is a corresponding satellite in parahydrogen it is weak and closer to the S(0)(0) band of the matrix. The conclusion of the paper is that interaction between guest rotation and the rotation of matrix molecules must be taken into account to explain the reduction of the rotation constants in orthodeuterium.
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| 23. |
- Ceponkus, J., et al.
(författare)
-
Structure and dynamics of small water clusters, trapped in inert matrices
- 2013
-
Ingår i: Chemical Physics Letters. - : Elsevier BV. - 0009-2614. ; 581, s. 1-9
-
Tidskriftsartikel (refereegranskat)abstract
- Recent matrix isolation (p-H-2, Ne, Ar, Kr) studies of water clusters made in Lund are reviewed. Gas phase positions of water cluster bands are estimated from matrix data. Intermolecular spectra of several isotopomers of the water dimer have been obtained, and approximate band strengths have been measured. Acceptor switching of the water dimer has been observed in matrices. A few intermolecular vibrations of (H2O)(3), (D2O)(3), (H2O)(4), and (D2O)(4) have been measured. The pseudorotation of the water trimer is not quenched in matrices, and pentamer pseudorotation appears to be fast as well. Spectra of partially deuterated water tetramers support a rigid cyclic tetramer structure. The hydrogen rotation in p-H-2 may interfere with guest vibrations at frequencies near the J = 2 <- J = 0 band of solid parahydrogen. (C) 2013 Elsevier B.V. All rights reserved.
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| 24. |
- Ceponkus, J., et al.
(författare)
-
The coupling between translation and rotation for monomeric water in noble gas matrices.
- 2013
-
Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 138:24
-
Tidskriftsartikel (refereegranskat)abstract
- The rotation of water in noble gas matrices has been studied. It is shown that the rotation-translation coupling model of Friedmann and Kimel predicts rotation line spacings, which are close to the experimental observations for H2O, D2O, and HDO, when gas phase rotation constants are used. The model gives intensity estimates in reasonable agreement with the observations for the local oscillator bands, which accompany the rotation spectrum. It also predicts the intensity variations in the bending region of H2O between neon, argon, and krypton matrices.
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| 25. |
- Ceponkus, J., et al.
(författare)
-
Water Tetramer, Pentamer, and Hexamer in Inert Matrices
- 2012
-
Ingår i: The Journal of Physical Chemistry Part A: Molecules, Spectroscopy, Kinetics, Environment and General Theory. - : American Chemical Society (ACS). - 1520-5215. ; 116:20, s. 4842-4850
-
Tidskriftsartikel (refereegranskat)abstract
- The infrared spectrum of water, isolated in inert matrices, has been studied in the interval from 60 to 4000 cm(-1). Experiments with partially deuterated water combined with DFT (density functional theory) calculations have been used to investigate the structure of matrix-isolated water tetramer. A few, strong intermolecular fundamentals of the water tetramer have been observed. Mid-infrared bands due to deuterated pentamers and hexamers have been observed and are used to discuss the assignments of these water clusters.
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| 26. |
- Dalmo, Erika, et al.
(författare)
-
Targeting SOX2 in glioblastoma cells reveals heterogeneity in SOX2 dependency
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma (GBM) is a lethal disease with no curative treatment. SOX2 is a stem cell transcription factor which is widely expressed across human GBM tumors. Downregulation of SOX2 inhibits tumor formation and its depletion leads to a complete stop of cell proliferation. Despite its known important role in GBM, there is a lack of SOX2 overexpression studies in human GBM cells cultured under stem cell conditions. Previous work in our lab suggests that SOX2 levels need to be precisely maintained for GBM cells to thrive. In this project, we have investigated how altered SOX2 expression affects primary human GBM lines. We found that elevated SOX2 expression inhibited proliferation in a dose-dependent manner in three out of four GBM cell lines. Global gene expression in the resistant line was shifted towards that of the proliferation-inhibited lines upon SOX2 induction. However, SOX2 induction also led to an increase in a GBM stem cell injury response phenotype, which was not present in proliferation-inhibited lines. Furthermore, CRISPR/Cas9-mediated SOX2 knockout revealed a SOX2 independence in the resistant cell line, where SOX2-negative cells could be propagated both in vitro and in vivo.
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| 27. |
- Ganat, Yosif M., et al.
(författare)
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Identification of embryonic stem cell-derived midbrain dopaminergic neurons for engraftment
- 2012
-
Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 122:8, s. 2928-2939
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Tidskriftsartikel (refereegranskat)abstract
- Embryonic stem cells (ESCs) represent a promising source of midbrain dopaminergic (DA) neurons for applications in Parkinson disease. However, ESC-based transplantation paradigms carry a risk of introducing inappropriate or tumorigenic cells. Cell purification before transplantation may alleviate these concerns and enable identification of the specific DA neuron stage most suitable for cell therapy. Here, we used 3 transgenic mouse ESC reporter lines to mark DA neurons at 3 stages of differentiation (early, middle, and late) following induction of differentiation using Hes5::GFP, Nurr1::GFP, and Pitx3::YFP transgenes, respectively. Transplantation of FACS-purified cells from each line resulted in DA neuron engraftment, with the mid-stage and late-stage neuron grafts being composed almost exclusively of midbrain DA neurons. Mid-stage neuron cell grafts had the greatest amount of DA neuron survival and robustly induced recovery of motor deficits in hemiparkinsonian mice. Our data suggest that the Nurrl(+) stage (middle stage) of neuronal differentiation is particularly suitable for grafting ESC-derived DA neurons. Moreover, global transcriptome analysis of progeny from each of the ESC reporter lines revealed expression of known midbrain DA neuron genes and also uncovered previously uncharacterized midbrain genes. These data demonstrate remarkable fate specificity of ESC-derived DA neurons and outline a sequential stage-specific ESC reporter line paradigm for in vivo gene discovery.
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| 28. |
- Goodrose-Flores, C, et al.
(författare)
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High-protein compared with standard parenteral nutrition in palliative cancer care
- 2022
-
Ingår i: BMJ supportive & palliative care. - : BMJ. - 2045-4368 .- 2045-435X. ; 12:3, s. 332-338
-
Tidskriftsartikel (refereegranskat)abstract
- High-protein parenteral nutrition (PN) has been developed to counteract muscle loss in patients with cancer treated with PN. Nevertheless, it is not clear if high-protein PN is as safe as standard PN in patients with palliative cancer. Our primary aim was to compare the proportion of patients with elevated liver enzymes between high-protein and standard PN in patients with palliative cancer enrolled to Medical Home Care. Our secondary aim was to compare the two treatments with regard to weight and albumin levels during treatment.MethodsMedical records from 2016 to 2018 were retrospectively reviewed to identify palliative cancer patients that had received PN for more than 3 weeks. Data on weight, height, albumin, liver enzymes, socioeconomic factors and dietitian consultations were collected at baseline and after 3–8 weeks of PN treatment. The odds of having elevated liver enzymes or having a maintained weight and/or stable albumin levels were calculated using logistic regression.Results20 patients treated with high-protein PN were compared with 104 patients treated with standard PN. Patients treated with high-protein PN had a significantly higher weight at follow-up compared with patients treated with standard PN (p<0.05). There was no significant difference in the proportion of patients with elevated liver enzymes (OR 0.20; 95% CI 0.02 to 1.86), or maintained weight and/or albumin levels (OR 1.62; 95% CI 0.46 to 5.76) between high-protein and standard PN.ConclusionHigh-protein PN was as safe, and at least as effective, as standard PN to patients with palliative cancer.
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| 29. |
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| 30. |
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| 31. |
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| 32. |
- Kitambi, Satish Srinivas, et al.
(författare)
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Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule
- 2014
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 157:2, s. 313-328
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with marginal life expectancy. Based on the assumption that GBM cells gain functions not necessarily involved in the cancerous process, patient-derived glioblastoma cells (GCs) were screened to identify cellular processes amenable for development of targeted treatments. The quinine-derivative NSC13316 reliably and selectively compromised viability. Synthetic chemical expansion reveals delicate structure-activity relationship and analogs with increased potency, termed Vacquinols. Vacquinols stimulate death by membrane ruffling, cell rounding, massive macropinocytic vacuole accumulation, ATP depletion, and cytoplasmic membrane rupture of GCs. The MAP kinase MKK4, identified by a shRNA screen, represents a critical signaling node. Vacquinol-1 displays excellent in vivo pharmacokinetics and brain exposure, attenuates disease progression, and prolongs survival in a GBM animal model. These results identify a vulnerability to massive vacuolization that can be targeted by small molecules and point to the possible exploitation of this process in the design of anticancer therapies.
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| 33. |
- Lund, Lars H, et al.
(författare)
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Rationale and design of ENDEAVOR: A sequential phase 2b-3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction.
- 2023
-
Ingår i: European journal of heart failure. - 1879-0844.
-
Tidskriftsartikel (refereegranskat)abstract
- Mitiperstat (formerly AZD4831) is a novel selective myeloperoxidase inhibitor. Currently, no effective therapies target comorbidity-induced systemic inflammation, which may be a key mechanism underlying heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Circulating neutrophils secrete myeloperoxidase, causing oxidative stress, microvascular endothelial dysfunction, interstitial fibrosis, cardiomyocyte remodelling and diastolic dysfunction. Mitiperstat may therefore improve function of the heart and other organs, and ameliorate heart failure symptoms and exercise intolerance. ENDEAVOR is a combined, seamless phase 2b-3 study of the efficacy and safety of mitiperstat in patients with HFpEF/HFmrEF.In phase 2b, approximately 660 patients with heart failure and ejection fraction >40% are being randomized 1:1:1 to mitiperstat 2.5 mg, 5 mg or placebo for 48 weeks. Eligible patients have baseline 6-min walk distance (6MWD) of 30-400 m with a <50 m difference between screening and randomization and Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) ≤90 points at screening and randomization. The dual primary endpoints are change from baseline to week 16 in 6MWD and KCCQ-TSS. The sample size provides 85% power to detect placebo-adjusted improvements of 21 m in 6MWD and 6.0 points in KCCQ-TSS at overall two-sided alpha of 0.05. Safety is monitored throughout treatment, with a focus on maculopapular rash. In phase 3 of ENDEAVOR, approximately 820 patients will be randomized 1:1 to mitiperstat or placebo.ENDEAVOR is the first phase 2b-3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF.
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| 34. |
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| 35. |
- Matuszewski, Damian J., et al.
(författare)
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Image-Based Detection of Patient-Specific Drug-Induced Cell-Cycle Effects in Glioblastoma
- 2018
-
Ingår i: SLAS Discovery. - : Elsevier BV. - 2472-5560 .- 2472-5552. ; 23:10, s. 1030-1039
-
Tidskriftsartikel (refereegranskat)abstract
- Image-based analysis is an increasingly important tool to characterize the effect of drugs in large-scale chemical screens. Herein, we present image and data analysis methods to investigate population cell-cycle dynamics in patient-derived brain tumor cells. Images of glioblastoma cells grown in multiwell plates were used to extract per-cell descriptors, including nuclear DNA content. We reduced the DNA content data from per-cell descriptors to per-well frequency distributions, which were used to identify compounds affecting cell-cycle phase distribution. We analyzed cells from 15 patient cases representing multiple subtypes of glioblastoma and searched for clusters of cell-cycle phase distributions characterizing similarities in response to 249 compounds at 11 doses. We show that this approach applied in a blind analysis with unlabeled substances identified drugs that are commonly used for treating solid tumors as well as other compounds that are well known for inducing cell-cycle arrest. Redistribution of nuclear DNA content signals is thus a robust metric of cell-cycle arrest in patient-derived glioblastoma cells.
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| 36. |
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| 37. |
- Merisaari, Joni, et al.
(författare)
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Monotherapy efficacy of blood-brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma
- 2020
-
Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 2:1
-
Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma is a fatal disease in which most targeted therapies have clinically failed. However, pharmacological reactivation of tumour suppressors has not been thoroughly studied as yet as a glioblastoma therapeutic strategy. Tumour suppressor protein phosphatase 2A is inhibited by non-genetic mechanisms in glioblastoma, and thus, it would be potentially amendable for therapeutic reactivation. Here, we demonstrate that small molecule activators of protein phosphatase 2A, NZ-8-061 and DBK-1154, effectively cross the in vitro model of blood-brain barrier, and in vivo partition to mouse brain tissue after oral dosing. In vitro, small molecule activators of protein phosphatase 2A exhibit robust cell-killing activity against five established glioblastoma cell lines, and nine patient-derived primary glioma cell lines. Collectively, these cell lines have heterogeneous genetic background, kinase inhibitor resistance profile and stemness properties; and they represent different clinical glioblastoma subtypes. Moreover, small molecule activators of protein phosphatase 2A were found to be superior to a range of kinase inhibitors in their capacity to kill patient-derived primary glioma cells. Oral dosing of either of the small molecule activators of protein phosphatase 2A significantly reduced growth of infiltrative intracranial glioblastoma tumours. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested glioblastoma cell lines, also significantly increased survival of mice bearing orthotopic glioblastoma xenografts. In summary, this report presents a proof-of-principle data for blood-brain barrier-permeable tumour suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background. These results also provide the first indications that protein phosphatase 2A reactivation might be able to challenge the current paradigm in glioblastoma therapies which has been strongly focused on targeting specific genetically altered cancer drivers with highly specific inhibitors. Based on demonstrated role for protein phosphatase 2A inhibition in glioblastoma cell drug resistance, small molecule activators of protein phosphatase 2A may prove to be beneficial in future glioblastoma combination therapies.
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| 38. |
- Mitchell, Jonathan S., et al.
(författare)
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Genome-wide association study identifies multiple susceptibility loci for multiple myeloma
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P = 1.31 x 10(-8)), 6q21 (rs9372120, P = 9.09 x 10(-15)), 7q36.1 (rs7781265, P = 9.71 x 10(-9)), 8q24.21 (rs1948915, P = 4.20 x 10(-11)), 9p21.3 (rs2811710, P = 1.72 x 10(-13)), 10p12.1 (rs2790457, P = 1.77 x 10(-8)), 16q23.1 (rs7193541, P = 5.00 x 10(-12)) and 20q13.13 (rs6066835, P = 1.36 x 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.
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| 39. |
- Niklasson, Mia, et al.
(författare)
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Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses
- 2017
-
Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 77:7, s. 1741-1752
-
Tidskriftsartikel (refereegranskat)abstract
- Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstreamsignaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na+, which compromised Na+-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas.
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| 40. |
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| 41. |
- Sablinskas, V, et al.
(författare)
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A high-resolution FT-IR study of the fundamental bands v(7), v(8), and v(18) of ethene secondary ozonide
- 2005
-
Ingår i: The Journal of Physical Chemistry Part A: Molecules, Spectroscopy, Kinetics, Environment and General Theory. - : American Chemical Society (ACS). - 1520-5215. ; 109:39, s. 8719-8723
-
Tidskriftsartikel (refereegranskat)abstract
- Ozonization reaction of ethene in neat film at 77 K was performed. Separation of ethene secondary ozonide from the other products of the reaction was performed by continuous pumping of the reactor. Only the products, which evaporated from the walls of the reactor at 185 K, were transferred to the gas cell. The high-resolution infrared absorption spectrum of gaseous ethene secondary ozonide (C2H4O3) in a static gas long-path absorption cell has been recorded in the 900-1100 cm(-1) spectral region at 185 K. The spectral resolution was 0.003 cm(-1). Analyses of the nu(7)(A) band at 1037.0 cm(-1), the nu(8)(A) band at 956.1 cm(-1), and the nu(18)(B) band at 1082.1 cm(-1) have been performed using the Watson Hamiltonian model (A, reduction; IIIr, representation). A set of ground-state rotational and quartic centrifugal distortion constants have been obtained, and upper state spectroscopic constants have been determined for the bands investigated. A local resonance observed in vis is explained as c-Coriolis interaction with nu(10) + nu(11).
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| 42. |
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| 43. |
- Schmidt, Linnéa, et al.
(författare)
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Case-specific potentiation of glioblastoma drugs by pterostilbene
- 2016
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:45, s. 73200-73215
-
Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM, astrocytoma grade IV) is the most common malignant primary brain tumor in adults. Addressing the shortage of effective treatment options for this cancer, we explored repurposing of existing drugs into combinations with potent activity against GBM cells. We report that the phytoalexin pterostilbene is a potentiator of two drugs with previously reported anti-GBM activity, the EGFR inhibitor gefitinib and the antidepressant sertraline. Combinations of either of these two compounds with pterostilbene suppress cell growth, viability, sphere formation and inhibit migration in tumor GBM cell (GC) cultures. The potentiating effect of pterostilbene was observed to a varying degree across a panel of 41 patient-derived GCs, and correlated in a case specific manner with the presence of missense mutation of EGFR and PIK3CA and a focal deletion of the chromosomal region 1p32. We identify pterostilbene-induced cell cycle arrest, synergistic inhibition of MAPK activity and induction of Thioredoxin interacting protein (TXNIP) as possible mechanisms behind pterostilbene's effect. Our results highlight a nontoxic stilbenoid compound as a modulator of anticancer drug response, and indicate that pterostilbene might be used to modulate two anticancer compounds in well-defined sets of GBM patients.
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| 44. |
- Schwartz, David A., et al.
(författare)
-
Placental Tissue Destruction and Insufficiency From COVID-19 Causes Stillbirth and Neonatal Death From Hypoxic-Ischemic Injury
- 2022
-
Ingår i: Archives of Pathology & Laboratory Medicine. - : COLL AMER PATHOLOGISTS. - 0003-9985 .- 1543-2165. ; 146:6, s. 660-676
-
Tidskriftsartikel (refereegranskat)abstract
- Context.-Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear. Objective.-To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Design.-Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19. Results.-Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs. Conclusions.-The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.
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| 45. |
- Schwartz, David A., et al.
(författare)
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Placental Tissue Destruction and Insufficiency From COVID-19 Causes Stillbirth and Neonatal Death From Hypoxic-Ischemic Injury : A Study of 68 Cases With SARS-CoV-2 Placentitis From 12 Countries
- 2022
-
Ingår i: Archives of Pathology & Laboratory Medicine. - : Archives of Pathology and Laboratory Medicine. - 0003-9985 .- 1543-2165. ; 146:6, s. 660-676
-
Tidskriftsartikel (refereegranskat)abstract
- Context: Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear.Objective: To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Design: Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19.Results: Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs.Conclusions: The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.
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| 46. |
- Svedlund, Sara, et al.
(författare)
-
Myeloperoxidase Inhibition in Heart Failure With Preserved or Mildly Reduced Ejection Fraction: SATELLITE Trial Results.
- 2023
-
Ingår i: Journal of cardiac failure. - 1532-8414. ; 30:1, s. 104-10
-
Tidskriftsartikel (refereegranskat)abstract
- Inflammation is a key driver of heart failure (HF) with preserved left ventricular ejection fraction (LVEF). AZD4831 inhibits extracellular myeloperoxidase, reduces inflammation and improves microvascular function in preclinical disease models.In this double-blind phase 2a study (SATELLITE; NCT03756285), patients with symptomatic HF, LVEF ≥40%, and elevated B-type natriuretic peptides were randomized 2:1 to once-daily oral AZD4831 5 mg or placebo for 90 days. We aimed to assess target engagement (primary endpoint: myeloperoxidase specific activity) and safety of AZD4831.Due to COVID-19, the study was terminated early after randomizing 41 patients (median age, 74.0 years; 53.7% male). Myeloperoxidase activity was reduced by >50% from baseline to day 30 and 90 in the AZD4831 group, with a placebo-adjusted reduction of 75% (95% confidence interval: 48, 88; nominal P <0.001). No improvements were noted in secondary/exploratory endpoints, apart from a trend in Kansas City Cardiomyopathy Questionnaire overall summary score. No deaths or treatment-related serious adverse events occurred. AZD4831 treatment-related adverse events were generalized maculopapular rash, pruritus and diarrhoea (all n=1).AZD4831 inhibited myeloperoxidase and was well tolerated in patients with HF and LVEF ≥40%. Efficacy findings were exploratory due to early termination but warrant further clinical investigation of AZD4831.Few treatments are available for patients with the forms of heart failure known as 'heart failure with preserved or mildly reduced ejection fraction'. Current treatments do not target inflammation, which may play an important role in this condition. We tested a new drug called AZD4831 (mitiperstat), which reduces inflammation by inhibiting the enzyme myeloperoxidase. Among the 41 patients in our clinical trial, AZD4831 had a good safety profile and inhibited myeloperoxidase by the expected amount. Results mean we can conduct further trials to see whether AZD4831 reduces the symptoms of heart failure and improves patients' ability to take physical exercise.
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| 47. |
- Weishaupt, Holger, et al.
(författare)
-
Loss of conservation of graph centralities in reverse-engineered transcriptional regulatory networks
- 2015
-
Ingår i: ASMDA 2015 Proceedings. - : ISAST: International Society for the Advancement of Science and Technology. - 9786185180058 ; , s. 1077-1091
-
Konferensbidrag (refereegranskat)abstract
- Graph centralities are often used to prioritize disease genes in transcrip-tional regulatory networks. Studies on small networks of experimentally validatedinteractions emphasize the general validity of this approach and extensions of suchndings have recently also been proposed for networks inferred from expression data.However, due to the noise inherent to expression data, it is largely unknown howwell centralities are preserved in such networks. Specically, while previous stud-ies have evaluated the performance of inference methods on synthetic expression, ithas yet to be established how the choice of method can aect individual centralitiesin the network. Here we compare two centralities between reference networks andnetworks inferred from corresponding simulated expression data using a number ofrelated methods. The results indicate that there exists only a modest conservationof centrality measures for the used inference methods. In conclusion, caution shouldbe exercised when inspecting centralities in reverse-engineered networks and furtherwork will be required to establish the use of such networks for prioritizing genes.
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| 48. |
- Weishaupt, Holger, et al.
(författare)
-
Loss of Conservation of Graph Centralities in Reverse-engineered Transcriptional Regulatory Networks
- 2017
-
Ingår i: Methodology and Computing in Applied Probability. - : Springer. - 1387-5841 .- 1573-7713. ; 19:4, s. 1095-1105
-
Tidskriftsartikel (refereegranskat)abstract
- Graph centralities are commonly used to identify and prioritize disease genes in transcriptional regulatory networks. Studies on small networks of experimentally validated protein-protein interactions underpin the general validity of this approach and extensions of such findings have recently been proposed for networks inferred from gene expression data. However, it is largely unknown how well gene centralities are preserved between the underlying biological interactions and the networks inferred from gene expression data. Specifically, while previous studies have evaluated the performance of inference methods on synthetic gene expression, it has not been established how the choice of inference method affects individual centralities in the network. Here, we compare two gene centrality measures between reference networks and networks inferred from corresponding simulated gene expression data, using a number of commonly used network inference methods. The results indicate that the centrality of genes is only moderately conserved for all of the inference methods used. In conclusion, caution should be exercised when inspecting centralities in reverse-engineered networks and further work will be required to establish the use of such networks for prioritizing disease genes.
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| 49. |
- Weishaupt, Holger, et al.
(författare)
-
Prediction of high centrality nodes from reverse-engineered transcriptional regulator networks
- 2016
-
Ingår i: Proocedings of the 4th Stochastic Modeling Techniques and Data Analysis International Conference with Demographics Workshop. ; , s. 517-531
-
Konferensbidrag (refereegranskat)abstract
- The prioritization of genes based on their centrality in biological networkshas emerged as a promising technique for the prediction of phenotype related genes.A number of methods have been developed to derive one such type of network, i.e.transcriptional regulatory networks, from expression data. In order to reliably prioritizegenes from such networks, it is crucial to investigate how well the inferencemethods reconstruct the centralities that exist in the true biological system. We haverecently reported that the correlation of centrality rankings between reference andinferred networks is only modest when using an unbiased inference approach. In thisstudy we extend on these results and demonstrate that the correlation remains modestalso when using a biased inference utilizing a priori information about transcriptionfactors. However, we show further that despite this lack of a strong correlation, theinferred networks still allow a signicant prediction of genes with high centralities inthe reference networks.
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| 50. |
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