1.
Björn, Niclas, et al.
(författare)
Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia
2020
Ingår i: The Pharmacogenomics Journal. - : Nature Publishing Group. - 1470-269X .- 1473-1150. ; 20:2, s. 179-191
Tidskriftsartikel (refereegranskat) abstract
Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10−5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10−4), rs6118 in SERPINA5 (P-value = 5.83 × 10−4), and rs5877 in SERPINC1 (P-value = 1.07 × 10−3), and the genes CAPZA2 (P-value = 4.03 × 10−4) and SERPINC1 (P-value = 1.55 × 10−3). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10−4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10−8), and decrease (OR = 66.82, P-value = 5.92 × 10−9). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.
2.
Chandolias, Konstantinos, et al.
(författare)
Protective effect of a reverse membrane bioreactor against toluene and naphthalene in anaerobic digestion
2022
Ingår i: Biotechnology and Applied Biochemistry. - : Wiley. - 1470-8744 .- 0885-4513. ; 69:3, s. 1267 -1274
Tidskriftsartikel (refereegranskat) abstract
Raw syngas contains tar contaminants including toluene and naphthalene, which inhibit its conversion to methane. Cell encasement in a hydrophilic reverse membrane bioreactor (RMBR) could protect the cells from hydrophobic contaminants. This study aimed to investigate the inhibition of toluene and naphthalene and the effect of using RMBR. In this work, toluene and naphthalene were added at concentrations of 0.5–1.0 and 0.1–0.2 g/L in batch operation. In continuous operation, concentration of 0–6.44 g/L for toluene and 0–1.28 g/L for naphthalene were studied. The results showed that no inhibition was observed in batch operation for toluene and naphthalene at concentrations up to 1 and 0.2 g/L, respectively. In continuous operation of free cell bioreactors (FCBRs), inhibition of toluene and naphthalene started at 2.05 and 0.63 g/L, respectively. When they were present simultaneously, inhibition of toluene and naphthalene occurred at concentrations of 3.14 and 0.63 g/L, respectively. In continuous RMBRs, no inhibition for toluene and less inhibition for naphthalene were observed, resulting in higher methane production from RMBR than that of FCBR. These results indicated that RMBR system gave a better protection effect against inhibitors compared with FCBR.
3.
Larsson, Julia, et al.
(författare)
Optimizing study design in LPS challenge studies for quantifying drug induced inhibition of TNF? response: Did we miss the prime time?
2022
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 176
Tidskriftsartikel (refereegranskat) abstract
In this work we evaluate the study design of LPS challenge experiments used for quantification of drug induced inhibition of TNF alpha response and provide general guidelines of how to improve the study design. Analysis of model simulated data, using a recently published TNF alpha turnover model, as well as the optimal design tool PopED have been used to find the optimal values of three key study design variables - time delay between drug and LPS administration, LPS dose, and sampling time points - that in turn could make the resulting TNF alpha response data more informative. Our findings suggest that the current rule of thumb for choosing the time delay should be reconsidered, and that the placement of the measurements after maximal TNF alpha response are crucial for the quality of the experiment. Furthermore, a literature study summarizing a wide range of published LPS challenge studies is provided, giving a broader perspective of how LPS challenge studies are usually conducted both in a preclinical and clinical setting.
4.
Morin, Maxim, et al.
(författare)
Skin hydration dynamics investigated by electrical impedance techniques in vivo and in vitro
2020
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 17218-
Tidskriftsartikel (refereegranskat) abstract
Skin is easily accessible for transdermal drug delivery and also attractive for biomarker sampling. These applications are strongly influenced by hydration where elevated hydration generally leads to increased skin permeability. Thus, favorable transdermal delivery and extraction conditions can be easily obtained by exploiting elevated skin hydration. Here, we provide a detailed in vivo and in vitro investigation of the skin hydration dynamics using three techniques based on electrical impedance spectroscopy. Good correlation between in vivo and in vitro results is demonstrated, which implies that simple but realistic in vitro models can be used for further studies related to skin hydration (e.g., cosmetic testing). Importantly, the results show that hydration proceeds in two stages. Firstly, hydration between 5 and 10 min results in a drastic skin impedance change, which is interpreted as filling of superficial voids in skin with conducting electrolyte solution. Secondly, a subtle impedance change is observed over time, which is interpreted as leveling of the water gradient across skin leading to structural relaxation/changes of the macromolecular skin barrier components. With respect to transdermal drug delivery and extraction of biomarkers; 1 h of hydration is suggested to result in beneficial and stable conditions in terms of high skin permeability and extraction efficiency.
5.
6.
Lundälv, Jörgen, 1966
(författare)
Bioterrorism och media
2004
Bok (övrigt vetenskapligt/konstnärligt) abstract
Attacker med biologiska och kemiska preparat är ett nytt hot mot institutioner i världen bl.a massmedia. I USA har ett antal medieföretag attackerats med brev som visat sig innehålla mjältbrand. I Sverige utsätts medier för hot och risker med jämna mellanrum. Denna guide om säkerhet och beredskap ger ny kunskap om vad bioterrorism innebär och vilka hotbilder som finns mot medieföretag i Sverige. Den vänder sig också till informationsstrateger vid myndigheter och företag liksom till hälso- och sjukvårdspersonal med intresse för epidemiologiska frågor. Guiden inleds med företal av Gorm Albrechtsen, f.d. chefredaktör vid Herning Folkeblad i Danmark som utsatts för misstänkta pulverbrev samt av Åke Sellström, avdelningschef vid Totalförsvarets forskningsinstitut (FOI) och expert på biologiska och kemiska vapen.
7.
Karlsson, Hanna, et al.
(författare)
Cell membrane damage and protein interaction induced by copper containing nanoparticles-Importance of the metal release process
2013
Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 313:1, s. 59-69
Tidskriftsartikel (refereegranskat) abstract
Cu-containing nanoparticles are used in various applications in order to e.g. achieve antimicrobial activities and to increase the conductivity of fluids and polymers. Several studies have reported on toxic effects of such particles but the mechanisms are not completely clear. The aim of this study was to investigate the interactions between cell membranes and well-characterized nanoparticles of CuO, Cu metal, a binary Cu-Zn alloy and micron-sized Cu metal particles. This was conducted via in vitro investigations of the effects of the nanoparticles on (i) cell membrane damage on lung epithelial cells (A549), (ii) membrane rupture of red blood cells (hemolysis), complemented by (iii) nanoparticle interaction studies with a model lipid membrane using quartz crystal microbalance with dissipation monitoring (QCM-D). The results revealed that nanoparticles of the Cu metal and the Cu-Zn alloy were both highly membrane damaging and caused a rapid (within 1 h) increase in membrane damage at a particle mass dose of 20 mu g/mL, whereas the CuO nanoparticles and the micron-sized Cu metal particles showed no such effect. At similar nanoparticle surface area doses, the nano and micron-sized Cu particles showed more similar effects. The commonly used LDH (lactate dehydrogenase) assay for analysis of membrane damage was found impossible to use due to nanoparticle-assay interactions. None of the particles induced any hemolytic effects on red blood cells when investigated up to high particle concentrations (1 mg/mL). However, both Cu and Cu-Zn nanopartides caused hemoglobin aggregation/precipitation, a process that would conceal a possible hemolytic effect. Studies on interactions between the nanoparticles and a model membrane using QCM-D indicated a small difference between the investigated particles. Results of this study suggest that the observed membrane damage is caused by the metal release process at the cell membrane surface and highlight differences in reactivity between metallic nanoparticles of Cu and Cu-Zn and nanoparticles of CuO.
8.
Harris, J. Milton, et al.
(författare)
Tuning drug release from polyoxazoline-drug conjugates
2019
Ingår i: European Polymer Journal. - : Elsevier BV. - 0014-3057. ; 120
Forskningsöversikt (refereegranskat) abstract
Poly(2-oxazoline)-drug conjugates with drugs attached via releasable linkages are being developed for drug delivery. Such conjugates with pendent ester linkages that covalently bind drugs to the polymer backbone exhibit significantly slower hydrolytic release rates in plasma than the corresponding PEG- and dextran-drug conjugates. The slow drug release rates in-vitro of these POZ-drug conjugates contribute to extended in-vivo pharmacokinetic profiles. In some instances, the release kinetics may be relatively sustained and ideal for once-a-week subcutaneous injection, whereas the native drug by itself may only have an in-vivo half-life of a few hours. The origin of this unusual kinetic and pharmacokinetic behavior is proposed here to involve folding of the POZ conjugate such that the relatively hydrophobic drug forms a central core, and the relatively hydrophilic polymer wraps around the core and slows enzymatic attack on the drug-polymer chemical linkage. Here we present evidence supporting this hypothesis and demonstrate how the hypothesis can be used to tune hydrolytic release rates and pharmacokinetics. Evidence for the folding hypothesis is taken from hydrolysis kinetics of a range of drugs in plasma, pharmacokinetics of a range of drugs following subcutaneous injection in laboratory animals, and nuclear magnetic resonance (NMR) studies showing folding of the POZ-rotigotine molecule. The drugs included in this study to test the hypothesis are: rotigotine, buprenorphine, dexanabinol, cannabidiol (CBD), Delta(9)-tetrahydrocannabinol (THC) and cannabigerol (CBG).
9.
Rolfö, Linda, et al.
(författare)
Predictors of Preference for the Activity-based Flexible Office
2019
Ingår i: Human Systems Engineering and Design. - Cham : Springer. - 9783030020521 - 9783030020538 ; 876, s. 547-553
Konferensbidrag (refereegranskat) abstract
Activity-based Flexible Offices (A-FOs) are implemented with varying degree of success. Employees relocate from cell or open-plan offices, from different organizational backgrounds, varying design and implementation processes, and have different types of work tasks. This study aims at investigating whether preference for the A-FO correlate with these preconditions. The results from Chi-square tests and Spearman’s non-parametric correlation of post-relocation questionnaires distributed to 11 A-FO sites, showed that a high preference for the A-FO correlated strongest with an A-FO preference prior to relocation, being a former open-plan office occupier and with frequent performance of innovation. Low preference for the A-FO correlated with frequent performance of concentration demanding tasks. Working with tasks with high confidentiality did not predict the preference ratings.
10.
Sandin, Gustav A, 1983, et al.
(författare)
Environmental evaluation of a clear coating for wood: toxicological testing and life cycle assessment
2012
Ingår i: PRA's 8th International Woodcoatings Congress (oral presentation and confereence proceeding paper).
Konferensbidrag (övrigt vetenskapligt/konstnärligt) abstract
WoodLife is an on-going project under the EU Seventh Framework Programme aimed at developing a water-based clear coating for exterior wood products. Adding nanoparticles to a conventional coating could improve its UV-protecting properties, thus decreasing the need for maintenance of coated wood products. Wood products could thereby replace non-wood alternatives, which could result in lower environmental impacts.This paper describes an environmental evaluation carried out within the WoodLife project, in which we test whether the nanoparticles are toxic for the bacteria Vibrio fischeri, and use Life Cycle Assessment (LCA) to map the environmental consequences of applying the coating on a wood product. This goes beyond the scope of most environmental evaluations of nanotechnologies, which tend to include either an assessment of the possible toxicity of the nanomaterial or an LCA.The toxicological testing indicates low ecotoxicity of the nanoparticles, but further development of suitable testing methods is warranted to enable a full ecotoxicological evaluation. The LCA shows that a wooden window frame with the new coating can be environmentally superior to plastic and aluminium window frames. However, the potential in part depends on variables such as recycling rates and disposal practices, which are highly uncertain for future products with long service lives.
