| 1. |
- Holmgren, Gustav, 1983-, et al.
(författare)
-
Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells
- 2015
-
Ingår i: Toxicology. - : Elsevier. - 0300-483X .- 1879-3185. ; 328, s. 102-111
-
Tidskriftsartikel (refereegranskat)abstract
- Doxorubicin is a chemotherapeutic agent indicated for the treatment of a variety of cancer types, including leukaemia, lymphomas, and many solid tumours. The use of doxorubicin is, however, associated with severe cardiotoxicity, often resulting in early discontinuation of the treatment. Importantly, the toxic symptoms can occur several years after the termination of the doxorubicin administration. In this study, the toxic effects of doxorubicin exposure have been investigated in cardiomyocytes derived from human embryonic stem cells (hESC). The cells were exposed to different concentrations of doxorubicin for up to 2 days, followed by a 12 day recovery period. Notably, the cell morphology was altered during drug treatment and the cells showed a reduced contractile ability, most prominent at the highest concentration of doxorubicin at the later time points. A general cytotoxic response measured as Lactate dehydrogenase leakage was observed after 2 days' exposure compared to the vehicle control, but this response was absent during the recovery period. A similar dose-dependant pattern was observed for the release of cardiac specific troponin T (cTnT) after 1 day and 2 days of treatment with doxorubicin. Global transcriptional profiles in the cells revealed clusters of genes that were differentially expressed during doxorubicin exposure, a pattern that in some cases was sustained even throughout the recovery period, suggesting that these genes could be used as sensitive biomarkers for doxorubicin-induced toxicity in human cardiomyocytes. The results from this study show that cTnT release can be used as a measurement of acute cardiotoxicity due to doxorubicin. However, for the late onset of doxorubicin-induced cardiomyopathy, cTnT release might not be the most optimal biomarker. As an alternative, some of the genes that we identified as differentially expressed after doxorubicin exposure could serve as more relevant biomarkers, and may also help to explain the cellular mechanisms behind the late onset apoptosis associated with doxorubicin-induced cardiomyopathy.
|
|
| 2. |
- Kettunen, Petronella, et al.
(författare)
-
Genetic Variants of GSK3B are Associated with Biomarkers for Alzheimer's Disease and Cognitive Function
- 2015
-
Ingår i: Journal of Alzheimers Disease. - 1387-2877. ; 44:4, s. 1313-1322
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Glycogen synthase kinase 3 beta (GSK3B) is the major kinase phosphorylating tau protein. Hyperphosphorylated tau is one of the hallmarks of Alzheimer's disease (AD). Despite extensive research, the role of GSK3B in AD pathogenesis is not fully understood.Objective: To evaluate possible associations between gene variants of GSK3B and risk of AD. Methods: Twelve GSK3B tag single-nucleotide polymorphisms (SNPs), together with the previously AD-associated rs334558, were analyzed in 583 AD patients and 673 controls. Analyses on single marker and haplotype levels were done to relate to risk of AD, Mini-Mental State Examination (MMSE) scores, and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau (P-tau(181)), and amyloid-beta (A beta(42)).Results: After correction for multiple testing, we found a number of associations of gene variants with CSF biomarker levels and cognitive function in the AD patients. Firstly, rs334558 was associated with elevated T-tau levels (p(c) = 0.04). Next, rs1154597 showed association with reducedA beta(42) levels (pc = 0.007). Lastly, rs3107669was associated with lower MMSE scores (p(c) = 0.03). In addition, one more SNP was nominally significantly associated with reduced A beta(42) levels and another was associated with reduced MMSE.Conclusion: We found GSK3B gene variants associated with cognitive function and CSF biomarkers T-tau and A beta(42). To our knowledge, this is the first time GSK3B has been associated with cognitive function or CSF biomarkers reflecting neuronal degeneration (T-tau) and brain amyloid load (A beta(42)). The regulation of GSK3B needs to be investigated further, to fully understand how these GSK3B gene variants are involved in AD pathogenesis.
|
|
| 3. |
- Asplund, Annika, 1979-, et al.
(författare)
-
One Standardized Differentiation Procedure Robustly Generates Homogenous Hepatocyte Cultures Displaying Metabolic Diversity from a Large Panel of Human Pluripotent Stem Cells
- 2016
-
Ingår i: Stem Cell Reviews and Reports. - : Springer Science and Business Media LLC. - 1550-8943 .- 1558-6804. ; 12:1, s. 90-104
-
Tidskriftsartikel (refereegranskat)abstract
- Human hepatocytes display substantial functional inter-individual variation regarding drug metabolizing functions. In order to investigate if this diversity is mirrored in hepatocytes derived from different human pluripotent stem cell (hPSC) lines, we evaluated 25 hPSC lines originating from 24 different donors for hepatic differentiation and functionality. Homogenous hepatocyte cultures could be derived from all hPSC lines using one standardized differentiation procedure. To the best of our knowledge this is the first report of a standardized hepatic differentiation procedure that is generally applicable across a large panel of hPSC lines without any adaptations to individual lines. Importantly, with regard to functional aspects, such as Cytochrome P450 activities, we observed that hepatocytes derived from different hPSC lines displayed inter-individual variation characteristic for primary hepatocytes obtained from different donors, while these activities were highly reproducible between repeated experiments using the same line. Taken together, these data demonstrate the emerging possibility to compile panels of hPSC-derived hepatocytes of particular phenotypes/genotypes relevant for drug metabolism and toxicity studies. Moreover, these findings are of significance for applications within the regenerative medicine field, since our stringent differentiation procedure allows the derivation of homogenous hepatocyte cultures from multiple donors which is a prerequisite for the realization of future personalized stem cell based therapies.
|
|
| 4. |
- Holmgren, Sandra, et al.
(författare)
-
Resolving the taxonomic conundrum in Graphoderus of the east Palearctic with a key to all species (Coleoptera, Dytiscidae).
- 2016
-
Ingår i: ZooKeys. - 1313-2989 .- 1313-2970. ; :574, s. 113-142
-
Tidskriftsartikel (refereegranskat)abstract
- The Holarctic diving beetle genus Graphoderus (Dytiscinae, Aciliini) contains relatively few and well-known species but these may still be difficult to identify based on external characters. A taxonomic problem in the eastern Palearctic was discovered that relates to the Palearctic Graphoderus zonatus (Hoppe, 1795) and the Nearctic Graphoderus perplexus Sharp, 1882. Based on qualitative and quantitative characters, especially on male genitalia which have been poorly studied in the past, it is shown that eastern Palearctic specimens identified by previous authors as either of the two species in fact belongs to a third species. The synonymized name Graphoderus elatus Sharp, 1882, is reinstated as a valid species (stat. n.) and a lectotype is designated from the mixed syntype series. The male genitalia of all known Graphoderus species have been examined and an illustrated identification key to the genus is provided. The three species in the complex of focus, Graphoderus elatus, Graphoderus zonatus and Graphoderus perplexus are found to have allopatric distributions; Graphoderus perplexus in the Nearctic region, Graphoderus zonatus in the west Palearctic region and eastwards to the Yenisei-Angara river and Graphoderus elatus east of the Yenisei-Angara river. All previous records of either Graphoderus zonatus or Graphoderus perplexus in the east Palearctic, east of the Yenisei-Angara river turned out to be misidentified Graphoderus elatus. This conclusion also brings with it that dimorphic females, thought only to be present in the single subspecies Graphoderus zonatus verrucifer (CR Sahlberg, 1824), proved to be present also in a second species, Graphoderus elatus. The dimorphic female forms is either with dorsally smooth elytra and pronotum or conspicuously granulated elytra and wrinkly pronotum. As has been shown in Graphoderus zonatus verrucifer there is a correlation between the occurrence of granulate female forms in a population and an increase in the number of adhesive discs on pro- and mesotarsus in males within Graphoderus elatus.
|
|
| 5. |
- Holmgren, Sandra, et al.
(författare)
-
Resolving the taxonomic conundrum in Graphoderus of the east Palearctic with a key to all species (Coleoptera, Dytiscidae)
- 2016
-
Ingår i: ZooKeys. - : Pensoft Publishers. - 1313-2989 .- 1313-2970. ; :574, s. 113-142
-
Tidskriftsartikel (refereegranskat)abstract
- The Holarctic diving beetle genus Graphoderus (Dytiscinae, Aciliini) contains relatively few and well-known species but these may still be difficult to identify based on external characters. A taxonomic problem in the eastern Palearctic was discovered that relates to the Palearctic G. zonatus (Hoppe, 1795) and the Nearctic G. perplexus Sharp, 1882. Based on qualitative and quantitative characters, especially on male genitalia which have been poorly studied in the past, it is shown that eastern Palearctic specimens identified by previous authors as either of the two species in fact belongs to a third species. The synonymized name G. elatus Sharp, 1882, is reinstated as a valid species (stat. n.) and a lectotype is designated from the mixed syntype series. The male genitalia of all known Graphoderus species have been examined and an illustrated identification key to the genus is provided. The three species in the complex of focus, G. elatus, G. zonatus and G. perplexus are found to have allopatric distributions; G. perplexus in the Nearctic region, G. zonatus in the west Palearctic region and eastwards to the Yenisei-Angara river and G. elatus east of the Yenisei-Angara river. All previous records of either G. zonatus or G. perplexus in the east Palearctic, east of the Yenisei-Angara river turned out to be misidentified G. elatus. This conclusion also brings with it that dimorphic females, thought only to be present in the single subspecies G. zonatus verrucifer (CR Sahlberg, 1824), proved to be present also in a second species, G. elatus. The dimorphic female forms is either with dorsally smooth elytra and pronotum or conspicuously granulated elytra and wrinkly pronotum. As has been shown in G. z. verrucifer there is a correlation between the occurrence of granulate female forms in a population and an increase in the number of adhesive discs on pro- and mesotarsus in males within G. elatus.
|
|
| 6. |
- Höjer Holmgren, Karin, et al.
(författare)
-
Part 1 : Tracing Russian VX to its synthetic routes by multivariate statistics of chemical attribution signatures
- 2018
-
Ingår i: Talanta. - : Elsevier. - 0039-9140 .- 1873-3573. ; 186, s. 586-596
-
Tidskriftsartikel (refereegranskat)abstract
- Chemical attribution signatures (CAS) associated with different synthetic routes used for the production of Russian VX (VR) were identified. The goal of the study was to retrospectively determine the production method employed for an unknown VR sample. Six different production methods were evaluated, carefully chosen to include established synthetic routes used in the past for large scale production of the agent, routes involving general phosphorus-sulfur chemistry pathways leading to the agent, and routes whose main characteristic is their innate simplicity in execution. Two laboratories worked in parallel and synthesized a total of 37 batches of VR via the six synthetic routes following predefined synthesis protocols. The chemical composition of impurities and byproducts in each route was analyzed by GC/MS-EI and 49 potential CAS were recognized as important markers in distinguishing these routes using Principal Component Analysis (PCA). The 49 potential CAS included expected species based on knowledge of reaction conditions and pathways but also several novel compounds that were fully identified and characterized by a combined analysis that included MS-CI, MS-EI and HR-MS. The CAS profiles of the calibration set were then analyzed using partial least squares discriminant analysis (PLS-DA) and a cross validated model was constructed. The model allowed the correct classification of an external test set without any misclassifications, demonstrating the utility of this methodology for attributing VR samples to a particular production method. This work is part one of a three-part series in this Forensic VSI issue of a Sweden-United States collaborative effort towards the understanding of the CAS of VR in diverse batches and matrices. This part focuses on the CAS in synthesized batches of crude VR and in the following two parts of the series the influence of food matrices on the CAS profiles are investigated.
|
|
| 7. |
- Ramzy, Ihab S, et al.
(författare)
-
Early effect of surgical revascularisation on left ventricular twist function
- 2015
-
Ingår i: International Cardiovascular Forum Journal. - : Barcaray Publishing. - 2410-2636 .- 2409-3424. ; 4, s. 16-23
-
Tidskriftsartikel (refereegranskat)abstract
- <p style="margin: 0cm 0cm 10pt; text-align: justify;"> </p><p style="margin: 0cm 0cm 10pt; text-align: justify;"><span style="font-family: 'Times New Roman','serif';"><span style="font-size: medium;">The direct effect of coronary artery bypass graft (CABG) surgery on early recovery of myocardial function, particularly twist and rotation is not well studied. </span></span></p><p style="margin: 0cm 0cm 10pt; text-align: justify;"> </p><p style="margin: 0cm 0cm 10pt; text-align: justify;"><span style="font-family: 'Times New Roman','serif';"><span style="font-size: medium;">Aim: To assess the early response of the 3 myocardial components, circumferential, longitudinal and oblique to CABG in patients with isolated coronary disease.</span></span></p><p style="margin: 0cm 0cm 10pt; text-align: justify;"> </p><p style="margin: 0cm 0cm 10pt; text-align: justify;"><span style="font-family: 'Times New Roman','serif';"><span style="font-size: medium;">Methods: We studied 14 patients, age 64±10 years, before CABG and before hospital discharge using various Doppler echocardiographic techniques including speckle tracking, and compared them with 28 age matched controls.</span></span></p><p style="margin: 0cm 0cm 10pt; text-align: justify;"> </p><p style="margin: 0cm 0cm 10pt; text-align: justify;"><span style="font-family: 'Times New Roman','serif';"><span style="font-size: medium;">Results: Before surgery: Compared to controls, patients had significantly reduced LVEF (p=0.01) but maintained stroke volume (SV) (p=0.5). Diastolic LV function indices were statistically abnormal (p=0.01). LV lateral wall long axis amplitude and myocardial systolic velocities were both reduced (p=0.01) as was septal amplitude of motion (p=0.05). LV peak global longitudinal strain (GLS) was reduced as were systolic and early diastolic global longitudinal strain rates (p=0.01 for all). LV peak basal and apical rotations, twist and torsion were not different. Q-peak basal rotation was shorter than controls (p=0.01).</span></span></p><p style="margin: 0cm 0cm 10pt; text-align: justify;"> </p><p style="margin: 0cm 0cm 10pt; text-align: justify;"><span style="font-family: 'Times New Roman','serif';"><span style="font-size: medium;">After surgery: None of these measurements changed except peak GLS which further reduced (p=0.01). Pre-operatively, SV correlated with global LV function: twist (r= -0.65, p=0.01), and LV torsion (r=-0.66, p=0.01) but LVEF did not correlate with either. Post-operatively, SV correlated with E/A ratio (r=0.66, p=0.01), and the time interval Q- peak basal rotation rate (r=0.8, p=0.002).</span></span></p><p style="margin: 0cm 0cm 10pt; text-align: justify;"> </p><p style="margin: 0cm 0cm 10pt; text-align: justify;"><span style="font-family: 'Times New Roman','serif';"><span style="font-size: medium;">Conclusion: CABG does not result in significant early segmental LV functional improvement along its three myocardial components, but SV becomes dependent on early basal rotation and filling pressures.</span></span></p><p style="margin: 0cm 0cm 10pt; text-align: justify;"> </p>
|
|
| 8. |
- Raúl Sitoe, Sandra, 1979-, et al.
(författare)
-
Paleo-environment and flooding of the Limpopo River-plain, Mozambique, between c. AD 1200-2000
- 2015
-
Ingår i: Catena (Cremlingen. Print). - : Elsevier BV. - 0341-8162 .- 1872-6887. ; 126, s. 105-116
-
Tidskriftsartikel (refereegranskat)abstract
- Multi-proxy analysis was performed on a radiocarbon-dated core, collected from a relic oxbow lake in theLimpopo River-plain, Mozambique, with the aim to reconstruct paleo-environment and past flooding of thelower river system over the past c. 800 years. An additional objective was to evaluate and investigate the potentialuse of different proxies as recorders of paleo-flooding events and paleo-environmental variability within thefloodplain. The proxies applied in this study were: mineral magnetic properties, grain-size distribution, organiccarbon content and diatom microfossil assemblages.We found that sediment grain-size and mineral magneticproperties of the minerogenic fraction were the most sensitive proxies in terms of detecting signals from highintensityriver-discharge events. In the 800 year long sequence, variations in sand content, magnetic susceptibilityand saturation isothermal remnant magnetization suggest at least four major flooding events at the siteduring the reconstructed period; in the mid-1200, late-1300, mid-1500 AD and during the last century. Thediatom proxy reflects the development of the site from an open oxbow lake to a mainly terrestrial area. Thediatom assemblage indicates that open lake conditions prevailed at the site between c. AD 1200–1400, withperiodic inundation by marine water, most likely due to late Holocene sea-level changes. From c. AD 1400 andonwards, diatoms were rarely deposited at the site, which indicates drier conditions. This was a result of soilformation and gradual in-filling of the lake, a processwhich possiblywas accentuated by a regionally dry climatesituation. Our study shows that oxbow lakes and the proxies used here have great potential for reconstructingflooding events, a knowledge that is crucial for potential prediction and mitigation of flooding events inMozambique in the future. Although chronological uncertainties limit comparisons to other paleoenvironmentalrecords, it seems that the flooding events recorded at our site occurred both during regionallywet and dry periods. Our data infer however, that flooding was probably more clearly recorded during thelake-stages than during infilled stage, probably as the terrestrial environment was more exposed to erosion.
|
|
| 9. |
- Siwe, Ulf, et al.
(författare)
-
Sea Traffic Management – Concepts and Components
- 2015
-
Ingår i: 14th International Conference on Computer and IT Applications in the Maritime Industries.
-
Konferensbidrag (refereegranskat)abstract
- This paper gives an overview of all components making up the Sea Traffic Management (STM) concept. STM builds upon information sharing in the whole maritime transport chain, where informationis shared as early as possible about intentions and reached states. Sea System Wide Information Management will provide an infrastructure for a regulated and federated approach to informationsharing. The functional sub-concepts are described: Strategic Voyage Management, Dynamic Voyage Management, Flow Management and Port Cooperative Decision Making. We will elaborate on how they complement each other and which benefits each of them has in regards to safety, environment and efficiency
|
|
