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  • 1.
    Aspegren, Anders
    et al.
    RISE Research Institutes of Sweden, Materials and Production, Product Realisation Methodology.
    Bäckdahl, Henrik
    RISE Research Institutes of Sweden, Materials and Production, Product Realisation Methodology.
    Storbritanniens satsning på tidig detektion av cancer med hjälp av flytande biopsier – beskrivning och analys2023Report (Other academic)
    Abstract [sv]

    Det pågår omfattande studier, framför allt i USA och Storbritannien, som undersöker möjligheterna att införa screening med hjälp av blodprover för tidig upptäckt av ett flertal cancerformer, så kallade MCED (Mulitple Cancer Early Detection). Ännu har inget faktiskt screeningsprogram med MCED-screening initierats i världen. I Sverige ställs idag höga krav på evidens från studier för att ett screeningprogram ska kunna införas. Det pågår studier som adresserar frågan om screening, men än så länge saknas mycket information. Med utgångspunkt i denna rapport kan därför inte en initiering av MCEDscreening i Sverige rekommenderas i dagsläget. För att vara i framkant bör Sverige dock följa området nogsamt. Grail är ett väletablerat företag som i augusti 2021 blev uppköpt av Illumina, ett företag som 2020 rapporterade en vinst på 2,34 miljarder USD. Företaget har stora ambitioner för framtida screeningprogram och kan bedömas ha de resurser som krävs att genomföra essentiella studier. De har säkrade medel och genomför projekt för att utveckla sin produkt för att fungera i en screeningsituation. Storbritanniens stora pågående studie ”NHS-Galleri Clinical Trial” beräknas publicera nya resultat under 2023. Om denna studie faller ut väl planeras en utvidgning av studien som ska omfatta en miljon personer. Denna större studie beräknas kunna avslutas 2030. Data att följa i nämnda ovanstående studie är bland annat: - Hur stor population ännu icke diagnostiserade utgör, i empiriska siffror - Utvecklingen av testmetoden gällande sensibilitet och sensitivitet - Patientnyttan, t.ex. ökar överlevnaden mot dagens siffror - Risken för överdiagnostik - Kostnader och logistik som kommer belasta sjukvården En problematik med MCED-screening är att testernas specificitet och sensitivitet behöver vara tillräckligt tillförlitliga för att det inte skall belasta snarare hjälpa samhället. Det är osannolikt att dessa värden kommer att vara 100-procentiga, men hur bra dessa värden bör vara innan man inför en screening är öppet för diskussion, däri ligger problematiken. I rapporten förklaras dessa begrepp i mer detalj. Det bör nämnas att Grail redan har kunnat presentera en ökad prestanda utifrån preliminära resultat ifrån pågående studier som presenterats i en så kallad sub-studie, där sensitivitet, sensibilitet och ”Tissue of Origin” (TOO) har förbättrats ytterligare gällande tolv olika cancerformer. Beräkningar i vår rapport har nyttjat dessa värden för att söka ge en bild över vad som kan förväntas vid ett införande av en Grail-MCED-screening i Sverige. För de tolv cancerformerna kan beräkningarna sammanfattas enligt; - Under förutsättning att det finns adekvat behandling att erbjuda vid tidigare diagnostik, kommer det ske en markant förskjutning av i vilket stadie som diagnostiserade individer detekteras och förhoppningsvis behandlas. Idag behandlas cirka 40 -45% av de cancerdiagnostiserade i stadie III/IV, att jämföras mot de beräknade 6% vid införande av årlig screening. - Ökningen av antalet individer som skulle överleva sin cancer uppskattas till mellan 3 - 5 000 individer, utöver de cirka 9 000 som överlever med hjälp av dagens diagnostik/behandling. - 25 – 35% kostnadsreducering både vad gäller direkta kostnader och samhällskostnader, extrapolerat från IHE rapport (1). Vi har dock inte tagit hänsyn till de kostnadsökningar ett införande av en MCED-screening skulle innebära. Det reella värdet av rapportens beräkningar bör vägas mot de empiriska data som kommer produceras av NHS studie av Grails metod. Starka avvikelser (”positiva/negativa”) från empiriska data kan då ligga till grund för om och i så fall hur pass snabbt man vill driva införande av MCED screening i Sverige. Rapportens sammantagna bedömning är att de av Socialstyrelsen uppsatta kriterier för införande av en screening, inte är uppfyllda i dagsläget. Men vi har även försökt visualisera vad som skulle komma att ske med dagens diagnostiserade cancerpatientgrupper om en MCED-screening införs i ålderspopulationen 40 – 80 år (96% av dagens diagnostiserade), på de tolv cancerformer som metoden visar bäst sensibilitet/sensitivitet mot. Dessa tolv cancerformer utgör 36% av dagens diagnostiserade patienter. Trots att ett införande av screening inte är att rekommendera i dagsläget, finns det alternativ att ta ställning till; - Endast avvakta utredningarna i Storbritannien (till 2023, eller till 2030). - Avvakta utredningarna men initiera samtal med beslutsfattare som styr över de ekonomiska medel som kan bistå med satsningar på större Grailtester i Sverige - Avvakta utredningarna, men initiera samtal med både NHS och Grail i syfte att behålla momentum i detta första initiativ till utredning. Författarnas uppfattning är att Grails teknik är signifikant och kommer med stor sannolikhet bedömas som tillämpbar för MCED-screening i framtiden.

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  • 2.
    Björn, Camilla
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik. University of Gothenburg, Sweden; Sahlgrenska Academy, Sweden.
    Antimicrobial peptides in the treatment of infectious and inflammatory conditions: Preclinical studies of mechanism of action, efficacy, and safety2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The rapid emergence of antibiotic-resistant microbes worldwide and the urgent need of new antimicrobial agents have stimulated interest in antimicrobial peptides (AMPs) as new therapeutics for treatment of infectious diseases. AMPs are present in all living species and constitute an important part of the innate immune system in multicellular organisms, including humans. AMPs display a remarkably broad spectrum of antimicrobial activity covering both Gram-positive and Gram-negative bacteria, including many antibiotic-resistant strains, as well as fungi, viruses, and protozoa. Further, in contrast to many conventional antibiotics, AMPs rapidly kill bacteria instead of just inhibiting bacterial growth. In addition, AMPs act as modulators of the innate immune system and, importantly, bacteria seem less efficient in developing resistance towards AMPs than towards conventional antibiotics. Together these properties make AMPs highly attractive as a new class of antimicrobials, with clinical potential also extending to diseases where inflammation is part of the pathology. The aim of this thesis was to study novel AMPs with respect to their mechanism of action (MOA), antimicrobial spectrum, propensity to select for resistance, and in vivo efficacy and safety. To achieve this, we used a number of in vitro and in vivo assays, together generating a comprehensive preclinical evaluation of the peptides. The hypothesis was that the AMPs in this thesis have potential to be developed as therapeutic agents for several infectious and inflammatory conditions, including treatment of skin and soft tissue infections and prevention of postsurgical adhesion formation. The results showed that all AMPs tested (i.e. PXL03, PXL150, HLR1r, and five variants of CEN1 HC-Br) had broad antimicrobial spectra in vitro with varying sensitivity to salt and serum. Furthermore, PXL150 caused a rapid permeabilization of bacterial membrane in vitro, indicating that this is at least one part of the MOA of this peptide. Under selection pressure in vitro, bacteria did not develop resistance to the peptides tested, i.e. PXL150 and CEN1 HC. Interestingly, all peptides showed anti-inflammatory activity by inhibiting the secretion of proinflammatory mediators from stimulated human cell lines. In addition, PXL01, PXL150, and HLR1r demonstrated fibrinolytic ability in vitro by suppressing the release of plasminogen activator inhibitor-1 (PAI-1). In ex vivo and in vivo skin/wound infection models, the peptides reduced the number of viable bacteria and yeast cells. Further, PXL01 decreased postsurgical adhesion formation in vivo. Notably, nonclinical safety studies showed that PXL150 was safe and well tolerated. In conclusion, several of the peptides evaluated in this thesis demonstrated a promising preclinical efficacy and safety profile motivating further development as drug candidates for local treatment of infectious and inflammatory conditions.

  • 3.
    Björn, Camilla
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik. Pergamum AB, Sweden; University of Gothenburg, Sweden.
    Mahlapuu, Margit
    Pergamum AB, Sweden; University of Gothenburg, Sweden.
    Mattsby-Baltzer, Inger
    University of Gothenburg, Sweden.
    Håkansson, Joakim
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik. Pergamum AB, Sweden.
    Anti-infective efficacy of the lactoferrin-derived antimicrobial peptide HLR1r2016In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 81, p. 21-28Article in journal (Refereed)
    Abstract [en]

    Antimicrobial peptides (AMPs) have emerged as a new class of drug candidates for the treatment of infectious diseases. Here we describe a novel AMP, HLR1r, which is structurally derived from the human milk protein lactoferrin and demonstrates a broad spectrum microbicidal action in vitro. The minimum concentration of HLR1r needed for killing ≥99% of microorganisms in vitro, was in the range of 3-50 μg/ml for common Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and for the yeast Candida albicans, when assessed in diluted brain-heart infusion medium. We found that HLR1r also possesses anti-inflammatory properties as evidenced by inhibition of tumor necrosis factor alpha (TNF-α) secretion from human monocyte-derived macrophages and by repression of interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1) secretion from human mesothelial cells, without any cytotoxic effect observed at the concentration range tested (up to 400 μg/ml). HLR1r demonstrated pronounced anti-infectious effect in in vivo experimental models of cutaneous candidiasis in mice and of excision wounds infected with MRSA in rats as well as in an ex vivo model of pig skin infected with S. aureus. In conclusion, HLR1r may constitute a new therapeutic alternative for local treatment of skin infections.

  • 4.
    Bloom, Erica
    et al.
    Lund University, Sweden.
    Grimsley, L. F.
    Tulane University SPHTM, USA.
    Pehrson, C.
    Lund University, Sweden.
    Lewis, J.
    Tulane University SPHTM, USA.
    Larsson, L.
    Lund University, Sweden.
    Molds and mycotoxins in dust from water-damaged homes in New Orleans after hurricane Katrina2009In: Indoor Air, ISSN 0905-6947, E-ISSN 1600-0668, Vol. 19, no 2, p. 153-158Article in journal (Refereed)
    Abstract [en]

    Dust collected in New Orleans homes mold-contaminated because of the flooding after hurricane Katrina was analyzed for molds and mycotoxins. The mycoflora was studied by cultivation and quantitative PCR for selected molds. The most commonly found mold taxa were Aspergillus, Cladosporium, and Penicillium. Verrucarol, a hydrolysis product of macrocyclic trichothecenes predominately produced by Stachybotrys spp. was identified in three dust samples by gas chromatography-tandem mass spectrometry, and sterigmatocystin (produced by various Aspergillus spp.) was found in two samples by high pressure liquid chromatography-tandem mass spectrometry. This is the first demonstration of mycotoxins in Katrina-associated dust samples. The analytical methods used represent valuable tools in further studies on bioaerosol exposure and health risks.

  • 5.
    Bloom, Erica
    et al.
    Lund University, Sweden.
    Nyman, E.
    Must, A.
    Pehrson, C.
    Larsson, L.
    Lund University, Sweden.
    Determination of mold and mycotoxins in building materials and house dust using mass spectrometry2009In: 9th International Conference and Exhibition - Healthy Buildings 2009, HB 2009Article in journal (Refereed)
    Abstract [en]

    Mycotoxins are toxic secondary metabolites frequently produced by molds in waterdamaged indoor environments. The objectives of this work were to characterize the mycoflora (by microscopy and culture) and to study the prevalence of selected mycotoxins and levels of fungal biomass (by gas chromatography- and high pressure liquid chromatography tandem mass spectrometry) in samples collected by building inspectors from water-damaged indoor environments in Sweden during a one-year period. Sixty-six percent of the analyzed building materials (n=100), 11% of the settled dust samples (n=18), and 51% of the cultured dust samples (n=37) were positive for at least one of the studied mycotoxins. Except in the case of gliotoxin, mycotoxin-positive building material samples contained 2-6 times more ergosterol than mycotoxin-negative samples. The study result shows that the majority of molds contaminating indoor materials in Swedish water-damaged buildings produce mycotoxins, and that mycotoxin-containing particles settle on surfaces above floor level in these environments.

  • 6.
    Bloom, Erica
    et al.
    Lund University, Sweden.
    Nyman, E.
    TEKOMO Byggnadskvalitet AB, Sweden.
    Must, A.
    IVL, Sweden.
    Pehrson, C.
    Lund University, Sweden.
    Larsson, L.
    Lund University, Sweden.
    Molds and mycotoxins in indoor environments — a survey in water-damaged buildings2009In: Journal of Occupational and Environmental Hygiene, ISSN 1545-9624, E-ISSN 1545-9632, Vol. 6, no 11, p. 671-678Article in journal (Refereed)
    Abstract [en]

    Mycotoxins are toxic, secondary metabolites frequently produced by molds in water-damaged indoor environments. We studied the prevalence of selected, potent mycotoxins and levels of fungal biomass in samples collected from water-damaged indoor environments in Sweden during a 1- year period. One hundred samples of building materials, 18 samples of settled dust, and 37 samples of cultured dust were analyzed for: (a) mycoflora by microscopy and culture; (b) fungal chemical marker ergosterol and hydrolysis products of macrocyclic trichothecenes and trichodermin (verrucarol and trichodermol) by gas chromatography-tandem mass spectrometry; and (c) sterigmatocystin, gliotoxin, aflatoxin B1, and satratoxin G and H by high performance liquid chromatography-tandem mass spectrometry. Sixty-six percent of the analyzed building materials samples, 11% of the settled dust samples, and 51% of the cultured dust samples were positive for at least one of the studied mycotoxins. In addition, except in the case of gliotoxin, mycotoxin-positive building material samples contained 2,6 times more ergosterol than mycotoxin-negative samples. We show that (a) molds growing on a range of different materials indoors in water-damaged buildings generally produce mycotoxins, and (b) mycotoxincontaining particles in mold-contaminated environments may settle on surfaces above floor level. The mass spectrometry methods used in this study are valuable tools in further research to survey mycotoxin exposure and investigate potential links with health effects. © 2009 JOEH, LLC.

  • 7.
    Boge, Lukas
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science. Chalmers University of Technology, Sweden.
    Bysell, Helena
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Ringstad, Lovisa
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Wennman, David
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Process Development, Analys och fastfas.
    Umerska, Anita
    University of Angers, France.
    Cassisa, Viviane
    CHU Angers, France.
    Eriksson, Jonny
    Uppsala University, Sweden.
    Joly-Guillou, Marie-Laure
    CHU Angers, France.
    Edwards, Katarina
    Uppsala University, Sweden.
    Andersson, Martin
    Chalmers University of Technology, Sweden.
    Lipid-based liquid crystals as carriers for antimicrobial peptides: Phase behavior and antimicrobial effect2016In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 32, no 17, p. 4217-4228Article in journal (Refereed)
    Abstract [en]

    The number of antibiotic-resistant bacteria is increasing worldwide, and the demand for novel antimicrobials is constantly growing. Antimicrobial peptides (AMPs) could be an important part of future treatment strategies of various bacterial infection diseases. However, AMPs have relatively low stability, because of proteolytic and chemical degradation. As a consequence, carrier systems protecting the AMPs are greatly needed, to achieve efficient treatments. In addition, the carrier system also must administrate the peptide in a controlled manner to match the therapeutic dose window. In this work, lyotropic liquid crystalline (LC) structures consisting of cubic glycerol monooleate/water and hexagonal glycerol monooleate/oleic acid/water have been examined as carriers for AMPs. These LC structures have the capability of solubilizing both hydrophilic and hydrophobic substances, as well as being biocompatible and biodegradable. Both bulk gels and discrete dispersed structures (i.e., cubosomes and hexosomes) have been studied. Three AMPs have been investigated with respect to phase stability of the LC structures and antimicrobial effect: AP114, DPK-060, and LL-37. Characterization of the LC structures was performed using small-angle X-ray scattering (SAXS), dynamic light scattering, ζ-potential, and cryogenic transmission electron microscopy (Cryo-TEM) and peptide loading efficacy by ultra performance liquid chromatography. The antimicrobial effect of the LCNPs was investigated in vitro using minimum inhibitory concentration (MIC) and time-kill assay. The most hydrophobic peptide (AP114) was shown to induce an increase in negative curvature of the cubic LC system. The most polar peptide (DPK-060) induced a decrease in negative curvature while LL-37 did not change the LC phase at all. The hexagonal LC phase was not affected by any of the AMPs. Moreover, cubosomes loaded with peptides AP114 and DPK-060 showed preserved antimicrobial activity, whereas particles loaded with peptide LL-37 displayed a loss in its broad-spectrum bactericidal properties. AMP-loaded hexosomes showed a reduction in antimicrobial activity.

  • 8.
    Bäckberg, Matilda
    et al.
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical and Pharmaceutical Toxicology.
    Vikingsson, Svante
    Linköping University, Sweden; National Board of Forensic Medicine, Sweden; RTI International, USA.
    Strandberg, Joakim
    Public Health Agency of Sweden, Sweden.
    Wall, Sara
    Public Health Agency of Sweden, Sweden.
    Åstrand, Anna
    Linköping University, Sweden.
    Karlsson, Hanna
    Linköping University, Sweden.
    Persson, Mattias
    National Board of Forensic Medicine, Sweden.
    Kronstrand, Robert
    Linköping University, Sweden; National Board of Forensic Medicine, Sweden.
    Green, Henrik
    Linköping University, Sweden; National Board of Forensic Medicine, Sweden.
    Using in vitro receptor activity studies of synthetic cannabinoids to support the risk assessment of new psychoactive substances – A Swedish strategy to protect public health from harm2023In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 348, article id 111691Article in journal (Refereed)
    Abstract [en]

    In the past 15 years, close to 1000 of new psychoactive substances (NPS) have been reported in Europe and globally. At the time of identification, data on safety, toxicity and carcinogenic potential of many NPS are not available or very limited. To work more efficiently, a strategy and collaboration between the Public Health Agency of Sweden (PHAS) and the National Board of Forensic Medicine was established involving in vitro receptor activity assays to demonstrate neurological activity of NPS. This report summarizes the first results on the synthetic cannabinoid receptor agonists (SCRAs), and subsequent actions taken by PHAS. A total of 18 potential SCRAs were selected by PHAS for in vitro pharmacological characterization. 17 compounds could be acquired and investigated for their activity on the human cannabinoid-1 (CB1) receptors expressed together with the AequoScreen system in CHO-K1 cells. Dose-response curves were established using eight different concentrations in triplicates at three occasions with JWH-018 as reference. For the MDMB-4en-PINACA, MMB-022, ACHMINACA, ADB-BUTINACA, 5F-CUMYL-PeGACLONE, 5C-AKB48, NM-2201, 5F-CUMYL-PINACA, JWH-022, 5Cl-AB-PINACA, MPhP-2201, 5F-AKB57 the half maximal effective concentration values ranged from 2.2 nM (5F-CUMYL-PINACA) to 171 nM (MMB-022). EG-018 and 3,5-AB-CHMFUPPYCA were none-active. The results contributed to 14 of these compounds being scheduled as narcotics in Sweden. In conclusion, many of the emerging SCRAs are potent activators of the CB1 receptor in vitro, although some lack activity or are partial agonists. The new strategy proved useful when data on psychoactive effects of the SCRAs under investigation were not available or limited. © 2023 The Authors

  • 9.
    Christensen, Gustav
    et al.
    University of Tübingen, Germany.
    Barut, Leon
    University of Tübingen, Germany.
    Urimi, Dileep
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Paquet-Durand, François
    University of Tübingen, Germany.
    Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems2021In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 13, no 7, article id 1013Article in journal (Refereed)
    Abstract [en]

    There is a strong need for innovative and efficient drug delivery systems for ocular therapy development. However, testing intravitreal drug delivery systems without using live animals is challenging. Ex vivo animal models offer an interesting alternative. We analyzed the potential of using fresh porcine eyes obtained from the local slaughterhouse as a model for testing the intravitreal biodistribution and retention of liposomes with or without polyethylene glycol (PEG) conjugation and with different surface charges. The histology of the eyes was analyzed to localize the liposomes, and it was found that liposomes with PEG absorbed rapidly on the retina (within 1 h), with positively charged and PEG-coated liposomes being retained for at least 24 h. In parallel, fluorophotometry was employed on intact eyes, to determine the pharmacokinetics of the fluorophore calcein, as a substitute for a small hydrophilic therapeutic compound. We found a 4.5-fold increase in the vitreous half-life of calcein loaded in liposomes, compared with the free solution. Retinal toxicity was addressed using murine-derived retinal explant cultures. Liposomes were non-toxic up to 500 µg/mL. Toxicity was observed at 5 mg/mL for anionic and cationic liposomes, with 2-fold and 2.5-fold increased photoreceptor cell death, respectively. Overall, we could show that important ocular drug delivery considerations such as pharmacokinetics and biodistribution can be estimated in ex vivo porcine eyes, and may guide subsequent in vivo experiments.

  • 10.
    Christensen, Gustav
    et al.
    University of Tübingen, Germany.
    Chen, Yiyi
    University of Tübingen, Germany.
    Urimi, Dileep
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Zizmare, Laimdota
    University Hospital Tübingen, Germany.
    Trautwein, Christoph
    University Hospital Tübingen, Germany.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Paquet-Durand, Francois
    University of Tübingen, Germany.
    Pyruvate-conjugation of PEGylated liposomes for targeted drug delivery to retinal photoreceptors2023In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 163, article id 114717Article in journal (Refereed)
    Abstract [en]

    Despite several promising candidates, there is a paucity of drug treatments available for patients suffering from retinal diseases. An important reason for this is the lack of suitable delivery systems that can achieve sufficiently high drug uptake in the retina and its photoreceptors. A promising and versatile method for drug delivery to specific cell types involves transporter-targeted liposomes, i.e., liposomes surface-coated with substrates for transporter proteins highly expressed on the target cell. We identified strong lactate transporter (monocarboxylate transporter, MCT) expression on photoreceptors as a potential target for drug delivery vehicles. To evaluate MCT suitability for drug targeting, we used PEG-coated liposomes and conjugated these with different monocarboxylates, including lactate, pyruvate, and cysteine. Monocarboxylate-conjugated and dye-loaded liposomes were tested on both human-derived cell-lines and murine retinal explant cultures. We found that liposomes conjugated with pyruvate consistently displayed higher cell uptake than unconjugated liposomes or liposomes conjugated with lactate or cysteine. Pharmacological inhibition of MCT1 and MCT2 reduced internalization, suggesting an MCT-dependent uptake mechanism. Notably, pyruvate-conjugated liposomes loaded with the drug candidate CN04 reduced photoreceptor cell death in the murine rd1 retinal degeneration model while free drug solutions could not achieve the same therapeutic effect. Our study thus highlights pyruvate-conjugated liposomes as a promising system for drug delivery to retinal photoreceptors, as well as other neuronal cell types displaying high expression of MCT-type proteins. © 2023 The Authors

  • 11.
    Christensen, Gustav
    et al.
    University of Tübingen, Germany.
    Urimi, Dileep
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. University of Iceland, Iceland.
    Lorenzo‐Soler, Laura
    University of Iceland, Iceland.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Paquet-Durand, François
    University of Tübingen, Germany.
    Ocular permeability, intraocular biodistribution of lipid nanocapsule formulation intended for retinal drug delivery2023In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 187, p. 175-183Article in journal (Refereed)
    Abstract [en]

    Recently, cGMP analogues have been investigated for the treatment of inherited retinal degenerations (IRD) using intravitreal injections. However, higher vitreous elimination rates limit the possibility to treat the retina with small molecule drugs. Here, we investigated the potential of lipid nanocapsules (LNCs) as vehicles to reduce clearance and prolong the delivery of cGMP analogue, CN03 to the retinal photoreceptors. Initially LNCs were investigated for both topical/periocular and intravitreal administration routes. While LNC-mediated drug permeation through the cornea proved to be too low for clinical applications, intravitreal application showed significant promise. Intravitreally administered LNCs containing fluorescent tracer in ex vivo porcine eyes showed complete intravitreal dispersal within 24 h. Ocular bio-distribution on histological sections showed that around 10 % of the LNCs had reached the retina, and 40 % accumulated in the ciliary body. For comparison, we used fluorescently labeled liposomes and these showed a different intraocular distribution with 48 % accumulated in the retina, and almost none were in the ciliary body. LNCs were then tested in retinal explants prepared from wild-type (WT) and rd1 mouse. In WT retina LNCs showed no significant toxic effects up to a concentration of 5 mg/mL. In rd1 retina, the LNC/CN03 formulation protected rd1 photoreceptors with similar efficacy to that of free CN03, demonstrating the usefulness of LNC/CN03 formulation in the treatment of IRD. Overall, our results indicate the suitability of LNCs for intraocular administration and drug delivery to both the retina and the ciliary body. © 2023 The Author(s)

  • 12.
    Colombo, Stefan
    et al.
    Uppsala University, Sweden.
    Brisander, Magnus
    XSpray Microparticles AB, Sweden.
    Haglöf, Jakob
    Uppsala University, Sweden.
    Sjövall, Peter
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik.
    Andersson, Per
    XSpray Microparticles AB, Sweden.
    Østergaard, Jesper
    University of Copenhagen, Denmark.
    Malmsten, Martin
    Uppsala University, Sweden.
    Matrix effects in nilotinib formulations with pH-responsive polymer produced by carbon dioxide-mediated precipitation2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 494, no 1, p. 205-217, article id 15114Article in journal (Refereed)
    Abstract [en]

    Factors determining the pH-controlled dissolution kinetics of nilotinib formulations with the pH-titrable polymer hydroxypropyl methylcellulose phthalate, obtained by carbon dioxide-mediated precipitation, were mechanistically examined in acid and neutral environment. The matrix effect, modulating the drug dissolution, was characterized with a battery of physicochemical methodologies, including ToF-SIMS for surface composition, SAXS/WAXS and modulated DSC for crystallization characterization, and simultaneous UV-imaging and Raman spectroscopy for monitoring the dissolution process in detail. The hybrid particle formulations investigated consisted of amorphous nilotinib embedded in a polymer matrix in single continuous phase, displaying extended retained amorphicity also under wet conditions. It was demonstrated by Raman and FTIR spectroscopy that the efficient drug dispersion and amorphization in the polymer matrix were mediated by hydrogen bonding between the drug and the phthalate groups on the polymer. Simultaneous Raman and UV-imaging studies of the effect of drug load on the swelling and dissolution of the polymer matrix revealed that high nilotinib load prevented matrix swelling on passage from acid to neutral pH, thereby preventing re-precipitation and re-crystallization of incorporated nilotinib. These findings provide a mechanistic foundation of formulation development of nilotinib and other protein kinase inhibitors, which are now witnessing an intense therapeutic and industrial attention due to the difficulty in formulating these compounds so that efficient oral bioavailability is reached.

  • 13.
    Cotman, A. E.
    et al.
    University of Ljubljana, Slovenia.
    Glinghammar, Björn
    RISE Research Institutes of Sweden, Bioeconomy and Health.
    Kikelj, D.
    University of Ljubljana, Slovenia.
    Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa2023In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 66, no 2, p. 1380-1425Article in journal (Refereed)
    Abstract [en]

    We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.

  • 14.
    Durcik, M.
    et al.
    University of Ljubljana, Slovenia.
    Glinghammar, Björn
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical and Pharmaceutical Toxicology.
    Sjöström, Eva
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Bohlin, Martin
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Oreskär, Joanna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Alvér, Sofie
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Peterlin Mašič, L.
    University of Ljubljana, Slovenia.
    New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus2023In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 66, no 6, p. 3968-3994Article in journal (Refereed)
    Abstract [en]

    A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125-0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1-4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated. © 2023 The Authors. 

  • 15.
    Fadeel, Bengt
    et al.
    Karolinska Institute, Sweden.
    Fornara, Andrea
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Material och ytteknik.
    Toprak, Muhammet S.
    KTH Royal Institute of Technology, Sweden.
    Bhattacharya, Kunal
    Karolinska Institute, Sweden.
    Keeping it real: The importance of material characterization in nanotoxicology2015In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 468, no 3, p. 498-503Article, review/survey (Refereed)
    Abstract [en]

    Nanomaterials are small and the small size and corresponding large surface area of nanomaterials confers specific properties, making these materials desirable for various applications, not least in medicine. However, it is pertinent to ask whether size is the only property that matters for the desirable or detrimental effects of nanomaterials? Indeed, it is important to know not only what the material looks like, but also what it is made of, as well as how the material interacts with its biological surroundings. It has been suggested that guidelines should be implemented on the types of information required in terms of physicochemical characterization of nanomaterials for toxicological studies in order to improve the quality and relevance of the published results. This is certainly a key issue, but it is important to keep in mind that material characterization should be fit-for-purpose, that is, the information gathered should be relevant for the end-points being studied.

  • 16.
    Flach, Carl-Fredrik
    et al.
    University of Gothenburg, Sweden.
    Hutinel, Marion
    University of Gothenburg, Sweden.
    Razavi, Mohammad
    University of Gothenburg, Sweden.
    Åhrén, Christina
    University of Gothenburg, Sweden; Region Västra Götaland, Sweden.
    Larsson, D G Joakim
    University of Gothenburg, Sweden.
    Monitoring of hospital sewage shows both promise and limitations as an early-warning system for carbapenemase-producing Enterobacterales in a low-prevalence setting.2021In: Water Research, ISSN 0043-1354, E-ISSN 1879-2448, Vol. 200, article id 117261Article in journal (Refereed)
    Abstract [en]

    Carbapenemase-producing Enterobacterales (CPE) constitute a significant threat to healthcare systems. Continuous surveillance is important for the management and early warning of these bacteria. Sewage monitoring has been suggested as a possible resource-efficient complement to traditional clinical surveillance. It should not least be suitable for rare forms of resistance since a single sewage sample contains bacteria from a large number of individuals. Here, the value of sewage monitoring in early warning of CPE was assessed at the Sahlgrenska University Hospital in Gothenburg, Sweden, a setting with low prevalence of CPE. Twenty composite hospital sewage samples were collected during a two-year period. Carbapenemase genes in the complex samples were analyzed by quantitative PCR and the CPE loads were assessed through cultures on CPE-selective agar followed by species determination as well as phenotypic and genotypic tests targeting carbapenemases of presumed CPE. The findings were related to CPE detected in hospitalized patients. A subset of CPE isolates from sewage and patients were subjected to whole genome sequencing. For three of the investigated carbapenemase genes, blaNDM, blaOXA-48-like and blaKPC, there was concordance between gene levels and abundance of corresponding CPE in sewage. For the other two analyzed genes, blaVIM and blaIMP, there was no such concordance, most likely due to the presence of those genes in non-Enterobacterales populating the sewage samples. In line with the detection of OXA-48-like- and NDM-producing CPE in sewage, these were also the most commonly detected CPE in patients. NDM-producing CPE were detected on a single occasion in sewage and isolated strains were shown to match strains detected in a patient. A marked peak in CPE producing OXA-48-like enzymes was observed in sewage during a few months. When levels started to increase there were no known cases of such CPE at the hospital but soon after a few cases were detected in samples from patients. The OXA-48-like-producing CPE from sewage and patients represented different strains, but they carried similar blaOXA-48-like-harbouring mobile genetic elements. In conclusion, sewage analyses show both promise and limitations as a complement to traditional clinical resistance surveillance for early warning of rare forms of resistance. Further evaluation and careful interpretation are needed to fully assess the value of such a sewage monitoring system.

  • 17. Garg, Neeraj
    Preparation of biphenyl compounds as estrogen receptor ligands for therapy: Preparation of biphenyl compounds as estrogen receptor ligands for therapy2013Patent (Other (popular science, discussion, etc.))
  • 18.
    Haeger-Eugensson, M.
    et al.
    IVL Swedish Environmental Research Institute, Sweden.
    Langer, S.
    IVL Swedish Environmental Research Institute, Sweden.
    Liljeberg, M.
    IVL Swedish Environmental Research Institute, Sweden.
    Must, A.
    IVL Swedish Environmental Research Institute, Sweden.
    Svennberg, K.
    IVL Swedish Environmental Research Institute, Sweden.
    Tang, L.
    IVL Swedish Environmental Research Institute, Sweden.
    Bloom, Erica
    IVL Swedish Environmental Research Institute, Sweden.
    Creating accurate boundary conditions for the analysis of the dynamic between indoor and outdoor climate2011In: 12th International Conference on Indoor Air Quality and Climate 2011, Vol. 3, p. 1963-1964Article in journal (Refereed)
  • 19.
    Hedberg, Y. S.
    et al.
    KTH Royal Institute of Technology, Sweden; Karolinska Institute, Sweden.
    Pradhan, S.
    KTH Royal Institute of Technology, Sweden.
    Cappellini, F.
    Karolinska Institute, Sweden.
    Karlsson, M. -E
    KTH Royal Institute of Technology, Sweden.
    Blomberg, Eva
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science. KTH Royal Institute of Technology, Sweden.
    Karlsson, H. L.
    Karolinska Institute, Sweden.
    Odnevall Wallinder, I.
    KTH Royal Institute of Technology, Sweden.
    Hedberg, J. F.
    KTH Royal Institute of Technology, Sweden.
    Electrochemical surface oxide characteristics of metal nanoparticles (Mn, Cu and Al) and the relation to toxicity2016In: Electrochimica Acta, ISSN 0013-4686, E-ISSN 1873-3859, Vol. 212, p. 360-371Article in journal (Refereed)
    Abstract [en]

    Most metal nanoparticles (NPs), except noble metal NPs, rapidly form a thin surface oxide in ambient conditions. The protective properties of these oxides improve or worsen depending on the environment, e.g., the human lung. Several properties, including the chemical/electrochemical stability and defect density, determine the capacity of these surface oxides to hinder the bulk metal from further oxidation (corrosion). The aim of this study was to investigate whether electrochemical surface oxide characterization of non-functionalized base metal NPs of different characteristics (Al, Mn and Cu) can assist in understanding their bioaccessibility (metal release) in cell media (DMEM+) and their cytotoxic properties following exposure in lung epithelial (A549) cells. The composition and valence states of surface oxides of metal NPs and their electrochemical activity were investigated using an electrochemical technique based on a graphite paste electrode to perform cyclic voltammetry in buffer solutions and open circuit potential measurements in DMEM+. The electrochemical surface oxide characterization was complemented and verified by Raman spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The open circuit potential trends in DMEM+ correlated well with metal release results in the same solution, and provided information on the kinetics of oxide dissolution in the case of Cu NPs. Extensive particle agglomeration in cell medium (DMEM+) was observed by means of photon-cross correlation spectroscopy for all metal NPs, with sedimentation taking place very quickly. As a consequence, measurements of the real dose of added non-functionalized metal NPs to cell cultures for cytotoxicity testing from a sonicated stock solution were shown necessary. The cytotoxic response was found to be strongly correlated to changes in physico-chemical and electrochemical properties of the surface oxides of the metal NPs, the most potent being Cu NPs, followed by Mn NPs. No cytotoxicity was observed for Al NPs. The electrochemical surface oxide characterization corresponded well with other tools commonly used for nanotoxicological characterization and provided additional information.

  • 20.
    Holmbäck, Jan
    et al.
    Stockholm University, Sweden; Lipidor AB, Sweden.
    Rinwa, Vibhu
    Stockholm University, Sweden; Lipidor AB, Sweden.
    Johansson, Jenny
    RISE Research Institutes of Sweden, Materials and Production.
    Håkansson, Joakim
    RISE Research Institutes of Sweden, Materials and Production. Gothenburg University, Sweden.
    Rinwa, Puneet
    Lipidor AB, Sweden.
    Carlsson, Anders
    MediGelium AB, Sweden.
    Herslöf, Bengt
    Lipidea AB, Sweden.
    Preclinical development of sodium fusidate antibiotic cutaneous spray based on water-free lipid formulation system2022In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 176, article id 106250Article in journal (Refereed)
    Abstract [en]

    Topical antibiotics are a key component in the management of mild to moderate skin and soft tissue infections. There are, however, concerns about the emerging bacterial resistance against topical antibacterial agents such as fusidic acid, due to the prolonged treatment period of its marketed dosage forms. Improving the efficacy of topical formulations could potentially shorten the treatment period and avoid the resistance growth. To provide a more effective drug delivery, a water-free lipid-based formulation system (AKVANO®) which can be applied by spraying, has been developed. In the current paper, different formulations containing sodium fusidate were evaluated for their in vitro skin permeability using artificial skin mimicking membranes and antibacterial properties using ex vivo and in vivo skin wound infection models. The novel formulations containing sodium fusidate showed a much higher skin permeation (up to 60% of nominal amount) than the commercially available Fucidin® cream (3%). These formulations also gave a significantly stronger antibacterial effect than Fucidin cream showing a clear dose-response relationship for the sodium fusidate content. A spray product based on the described formulation technology would therefore require a shorter treatment time and thereby lower the risk for the development of bacterial resistance. Spray administration of these formulations provides an even layer on the skin surface from which the solvent quickly evaporates and thereby facilitates a non-touch application where no rubbing is required. © 2022 The Authors

  • 21.
    Janosik, Tomasz
    et al.
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Berg, Robert
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Chemistry of Silepins and their Analogs Containing Group 14 Elements2021In: ARKIVOC, ISSN 1551-7004, E-ISSN 1551-7012, Vol. 2020, no 7, p. 379-400Article in journal (Refereed)
    Abstract [en]

    The chemistry of silepins and related seven-membered heterocycles containing group 14 elements is reviewed. 

  • 22.
    Karlsson, Staffan
    et al.
    AstraZeneca, Sweden.
    Sörensen, Henrik
    AstraZeneca, Sweden.
    Andersen, Sören M.
    AstraZeneca, Sweden.
    Cruz, Angele
    AstraZeneca, Sweden.
    Ryberg, Per
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Process Development.
    An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD27162016In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 20, no 2, p. 262-269Article in journal (Refereed)
    Abstract [en]

    A classical resolution of a racemic carboxylic acid through salt formation and an asymmetric hydrogenation of an α,β-unsaturated carboxylic acid were investigated in parallel to prepare an enantiomerically pure alkanoic acid used as a key intermediate in the synthesis of an antiplaque candidate drug. After an extensive screening of rhodium- and ruthenium-based catalysts, we developed a rhodium-catalyzed hydrogenation that gave the alkanoic acid with 90% ee, and after a subsequent crystallization with (R)-1-phenylethanamine, the ee was enriched to 97%. The chiral acid was then used in sequential Negishi and Suzuki couplings followed by basic hydrolysis of a nitrile to an amide to give the active pharmaceutical ingredient in 22% overall yield.

  • 23.
    Karsten, Stella
    et al.
    Karolinska Institute, Sweden.
    Fiskesund, Roland
    Karolinska Institute, Sweden.
    Zhang, Xing-Mei
    Karolinska Institute, Sweden.
    Marttila, Petra
    Karolinska Institute, Sweden.
    Sanjiv, Kumar
    Karolinska Institute, Sweden.
    Pham, Therese
    Karolinska Institute, Sweden.
    Rasti, Azita
    Karolinska Institute, Sweden.
    Bräutigam, Lars
    Karolinska Institute, Sweden.
    Almlöf, Ingrid
    Karolinska Institute, Sweden.
    Marcusson-Ståhl, Maritha
    Sandman, Carolina
    Platzack, Björn
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Harris, Robert A.
    Karolinska Institute, Sweden.
    Kalderén, Christina
    Karolinska Institute, Sweden.
    Cederbrant, Karin
    Helleday, Thomas
    Karolinska Institute, Sweden; University of Sheffield, United Kingdom.
    Warpman Berglund, Ulrika
    Karolinska Institute, Sweden; Oxcia AB, Sweden.
    MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells2022In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 29, no 1, p. 246-261Article in journal (Refereed)
    Abstract [en]

    T cell-driven diseases account for considerable morbidity and disability globally and there is an urgent need for new targeted therapies. Both cancer cells and activated T cells have an altered redox balance, and up-regulate the DNA repair protein MTH1 that sanitizes the oxidized nucleotide pool to avoid DNA damage and cell death. Herein we suggest that the up-regulation of MTH1 in activated T cells correlates with their redox status, but occurs before the ROS levels increase, challenging the established conception of MTH1 increasing as a direct response to an increased ROS status. We also propose a heterogeneity in MTH1 levels among activated T cells, where a smaller subset of activated T cells does not up-regulate MTH1 despite activation and proliferation. The study suggests that the vast majority of activated T cells have high MTH1 levels and are sensitive to the MTH1 inhibitor TH1579 (Karonudib) via induction of DNA damage and cell cycle arrest. TH1579 further drives the surviving cells to the MTH1low phenotype with altered redox status. TH1579 does not affect resting T cells, as opposed to the established immunosuppressor Azathioprine, and no sensitivity among other major immune cell types regarding their function can be observed. Finally, we demonstrate a therapeutic effect in a murine model of experimental autoimmune encephalomyelitis. In conclusion, we show proof of concept of the existence of MTH1high and MTH1low activated T cells, and that MTH1 inhibition by TH1579 selectively suppresses pro-inflammatory activated T cells. Thus, MTH1 inhibition by TH1579 may serve as a novel treatment option against autoreactive T cells in autoimmune diseases, such as multiple sclerosis.

  • 24.
    Kuna, V K
    et al.
    University of Gothenburg, Sweden.
    Padma, A M
    University of Gothenburg, Sweden.
    Håkansson, Joakim
    RISE - Research Institutes of Sweden, Bioscience and Materials, Chemistry and Materials.
    Nygren, J
    TATAA Biocenter, Sweden.
    Sjöback, R
    TATAA Biocenter, Sweden.
    Petronis, Sarunas
    RISE - Research Institutes of Sweden, Bioscience and Materials, Chemistry and Materials.
    Sumitran-Holgersson, S
    University of Gothenburg, Sweden.
    Significantly accelerated wound healing of full-thickness skin using a novel composite gel of porcine acellular dermal matrix and human peripheral blood cells2017In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, no 2, p. 293-307Article in journal (Refereed)
    Abstract [en]

    Herein, we report the fabrication of a novel composite gel from decellularized gal-gal-knockout porcine skin and human peripheral blood mononuclear cells (hPBMC) for full-thickness skin wound healing. Decellularized skin extracellular matrix (ECM) powder was prepared via chemical treatment, freeze-drying and homogenization. The powder was mixed with culture medium containing hyaluronic acid to generate a pig skin gel (PSG). The effect of the gel in regeneration of full-thickness wound was studied in nude mice. We found significantly accelerated wound closure already on day 15 in animals treated with PSG only or PSG+hPBMC as compared to untreated and hyaluronic acid treated controls (p<0.05). Addition of the hPBMC to the gel resulted in marked increase of host blood vessels as well as the presence of human blood vessels. At day 25, histologically, the wounds in animals treated with PSG only or PSG+hPBMC were completely closed as compared to controls. Thus, the gel facilitated generation of new skin with well arranged epidermal cells and restored bilayer structure of the epidermis and dermis. These results suggest that porcine skin ECM gel together with human cells may be a novel and promising biomaterial for medical applications especially for patients with acute and chronic skin wounds.

  • 25.
    Langer, S.
    et al.
    IVL, Sweden; University of Gothenburg, Sweden.
    Bekö, G.
    DTU Technical University of Denmark, Denmark.
    Bloom, Erica
    IVL, Sweden.
    Widheden, A.
    IVL, Sweden.
    Ekberg, L.
    Chalmers University of Technology, Sweden; CIT Energy Management AB, Sweden.
    Indoor air quality in passive and conventional new houses in Sweden2015In: Building and Environment, ISSN 0360-1323, E-ISSN 1873-684X, Vol. 93, no P1, p. 92-100Article in journal (Refereed)
    Abstract [en]

    The indoor environment was evaluated in 20 new passive houses and 21 new conventionally built houses during the 2012/2013 and 2013/2014 heating seasons. Temperature, relative humidity (RH), the concentrations of NO2, ozone, formaldehyde, volatile organic compounds (VOC) and viable microbiological flora were measured. Air exchange rates (AER) were estimated from the CO2 concentrations measured in the bedrooms. The median AER was slightly higher in the passive houses than in the conventional ones (0.68 h-1 vs. 0.60 h-1). The median concentrations in the passive and the conventional buildings were 10 and 12ÎŒg/m3 for NO2, 9.7 and 11 ÎŒg/m3 for ozone, 11 and 16ÎŒg/m3 for formaldehyde, and 270 and 150 ÎŒg/m3 for TVOC, respectively. Significant differences in the TVOC and formaldehyde concentrations between the two groups of buildings indicated substantial sources of TVOC present in the passive houses, while sources of formaldehyde may have been more pronounced in the conventional houses. In contrast to the passive houses, the indoor microbiological flora indicated possible mould or moisture problems in six (29%) of the conventionally built houses. When compared with the results previously reported for the Swedish housing stock, AERs and NO2 concentrations were significantly higher in both groups of newly built buildings, while formaldehyde concentrations were significantly lower in the passive houses. TVOC concentrations were not significantly different from those reported for the housing stock, although the most abundant individual VOCs were present mostly at higher concentrations in the new buildings.

  • 26.
    Langer, S.
    et al.
    IVL, SWeden.
    Bloom, Erica
    IVL, Sweden.
    Bekö, G.
    DTU Technical University of Denmark, Denmark.
    Indoor environment in Swedish passive houses2014Conference paper (Refereed)
    Abstract [en]

    The purpose of this study was to evaluate the indoor air quality (IAQ) in newly built low energy houses. Measurements were performed in 22 passive houses and 21 conventional buildings during 2012-2013 and 2013-2014 heating seasons. The measured parameters were temperature, relative humidity, concentration of CO2, NO2, formaldehyde, volatile organic compounds, and live microbiological flora. Air exchange rates (AER) were determined from the concentration-time profiles of CO2. The median AER was slightly higher in the passive houses than in conventional buildings (0.66 h-1 vs. 0.60 h-1). The median concentrations in passive houses and conventional buildings were 9.7 and 11 ÎŒg/m3, respectively, for NO2, 12 and 16 ÎŒg/m3 for formaldehyde, and 230 and 145 ÎŒg/m3 for TVOC. The indoor microbiological flora did not differ, with a few exceptions, from outdoors. The IAQ in the passive buildings was judged to be relatively good with regard to the parameters measured in this study.

  • 27.
    Langer, S.
    et al.
    IVL, Sweden.
    Moldanova, J.
    IVL, Sweden.
    Bloom, Erica
    RISE Research Institutes of Sweden, Built Environment, Building and Real Estate. IVL, Sweden.
    Österman, C.
    Linnaeus University, Sweden.
    Indoor environment on-board the swedish icebreaker oden2014Conference paper (Refereed)
    Abstract [en]

    The indoor air quality (IAQ) on-board the Swedish icebreaker Oden was examined during two field campaigns, in winter and in summer 2013. The measured parameters were temperature, relative humidity, air exchange rate and concentration of CO, CO2, NO, NO2, ozone, SO2, volatile organic compounds (VOC), formaldehyde, PAH, PM10, PM2.5 and submicron and ultrafine particles. Several indoor spaces of both living and working environments were investigated from the top to the bottom of the ship and outdoor air reference samples were collected at the same time. The results show in general that the IAQ on the ship is good with respect to the existing, recommended indoor air guideline values and occupational limit values. Concentrations in the living spaces were comparable with those in Swedish homes. The majority of the indoor air pollutants on the ship originated from the ship fuel evaporative emissions and operation of the main and auxiliary engines and boilers.

  • 28.
    Larsson, Lennart
    et al.
    Lund University, Sweden.
    Peitzsch, M.
    University Hospital Carl Gustav Carus, Germany.
    Must, Aime
    IVL, Sweden.
    Bloom, Erica
    IVL, Sweden.
    Evaluation of mold sanitation methods2011In: 12th International Conference on Indoor Air Quality and Climate 2011, Vol. 1, p. 821-822Article in journal (Refereed)
  • 29.
    López-Guajardo, A.
    et al.
    University of Sheffield, UK.
    Zafar, A.
    University of Sheffield, UK.
    Al Hennawi, K.
    University of Sheffield, UK.
    Rossi, V.
    Veneto Institute of Oncology IOV-IRCCS, Italy.
    Alrwaili, A.
    University of Sheffield, UK.
    Medcalf, J. D.
    University of Sheffield, UK.
    Dunning, M.
    University of Sheffield, UK.
    Nordgren, Niklas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Material and Surface Design.
    Pettersson, T.
    KTH Royal Institute of Technology, Sweden.
    Estabrook, I. D.
    University of Sheffield, UK; Technische Universität Dresden, Germany.
    Hawkins, R. J.
    University of Sheffield, UK; African Institute for Mathematical Sciences, Ghana.
    Gad, A. K. B.
    University of Sheffield, UK; University of Madeira, Portugal; Karolinska Institute, Sweden.
    Regulation of cellular contractile force, shape and migration of fibroblasts by oncogenes and Histone deacetylase 62023In: Frontiers in Molecular Biosciences, E-ISSN 2296-889X, Vol. 10, article id 1197814Article in journal (Refereed)
    Abstract [en]

    The capacity of cells to adhere to, exert forces upon and migrate through their surrounding environment governs tissue regeneration and cancer metastasis. The role of the physical contractile forces that cells exert in this process, and the underlying molecular mechanisms are not fully understood. We, therefore, aimed to clarify if the extracellular forces that cells exert on their environment and/or the intracellular forces that deform the cell nucleus, and the link between these forces, are defective in transformed and invasive fibroblasts, and to indicate the underlying molecular mechanism of control. Confocal, Epifluorescence and Traction force microscopy, followed by computational analysis, showed an increased maximum contractile force that cells apply on their environment and a decreased intracellular force on the cell nucleus in the invasive fibroblasts, as compared to normal control cells. Loss of HDAC6 activity by tubacin-treatment and siRNA-mediated HDAC6 knockdown also reversed the reduced size and more circular shape and defective migration of the transformed and invasive cells to normal. However, only tubacin-mediated, and not siRNA knockdown reversed the increased force of the invasive cells on their surrounding environment to normal, with no effects on nuclear forces. We observed that the forces on the environment and the nucleus were weakly positively correlated, with the exception of HDAC6 siRNA-treated cells, in which the correlation was weakly negative. The transformed and invasive fibroblasts showed an increased number and smaller cell-matrix adhesions than control, and neither tubacin-treatment, nor HDAC6 knockdown reversed this phenotype to normal, but instead increased it further. This highlights the possibility that the control of contractile force requires separate functions of HDAC6, than the control of cell adhesions, spreading and shape. These data are consistent with the possibility that defective force-transduction from the extracellular environment to the nucleus contributes to metastasis, via a mechanism that depends upon HDAC6. To our knowledge, our findings present the first correlation between the cellular forces that deforms the surrounding environment and the nucleus in fibroblasts, and it expands our understanding of how cells generate contractile forces that contribute to cell invasion and metastasis. Copyright © 2023 López-Guajardo, Zafar, Al Hennawi, Rossi, Alrwaili, Medcalf, Dunning, Nordgren, Pettersson, Estabrook, Hawkins and Gad.

  • 30.
    Mahlapuu, Margit
    et al.
    Promore Pharma AB, Sweden; University of Gothenburg, Sweden.
    Håkansson, Joakim
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik.
    Ringstad, Lovisa
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Björn, Camilla
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik. University of Gothenburg, Sweden.
    Antimicrobial peptides: An emerging category of therapeutic agents2016In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 6, no DEC, article id 194Article in journal (Refereed)
    Abstract [en]

    Antimicrobial peptides (AMPs), also known as host defense peptides, are short and generally positively charged peptides found in a wide variety of life forms from microorganisms to humans. Most AMPs have the ability to kill microbial pathogens directly, whereas others act indirectly by modulating the host defense systems. Against a background of rapidly increasing resistance development to conventional antibiotics all over the world, efforts to bring AMPs into clinical use are accelerating. Several AMPs are currently being evaluated in clinical trials as novel anti-infectives, but also as new pharmacological agents to modulate the immune response, promote wound healing, and prevent post-surgical adhesions. In this review, we provide an overview of the biological role, classification, and mode of action of AMPs, discuss the opportunities and challenges to develop these peptides for clinical applications, and review the innovative formulation strategies for application of AMPs.

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  • 31.
    Martínez, Claudia
    et al.
    Uppsala University, Sweden; University of Barcelona, Spain.
    Amery, Leanne
    AstraZeneca, UK.
    De Paoli, Giorgia
    University of Dundee, uk.
    Elofsson, Ulla
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Kwok, Stanley
    AstraZeneca, USA.
    López-Cabezas, Carmen
    Hospital Clínic Barcelona, Spain.
    Rosenberger, Marika
    Sanofi-Aventis Deutschland GmbH, Germany.
    Schoenau, Christian
    Sanofi-Aventis Deutschland GmbH, Germany.
    Wahlgren, Marie
    Lund University,Sweden.
    Paulsson, Mattias
    Uppsala University, Sweden.
    Examination of the Protein Drug Supply Chain in a Swedish University Hospital: Focus on Handling Risks and Mitigation Measures2023In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017Article in journal (Refereed)
    Abstract [en]

    Protein drugs, such as monoclonal antibodies, have proved successful in treating cancer and immune system diseases. The structural complexity of these molecules requires careful handling to ensure integrity and stability of the drug. In this study, a failure mode and effects analysis was performed based on a Gemba Walk method in a Swedish University Hospital. The Gemba Walk is focused on pharmacists observing the actual supply process steps from distributor, pharmacy cleanroom to patient administration. Relevant protein drugs are chosen based on sales statistics within the hospital and the corresponding wards were observed. Further is the Double Diamond design method used to identify major risks and deliver mitigation strategies. The study identified potential stress factors such as temperature, shock by impact, shaking, vibration and light exposure. There were also risks associated with porters’ and healthcare professionals’ lack of awareness and access to information. These risk factors may cause loss of efficacy and quality of the protein drug, potentially leading to patient safety concerns. In this study, a simulation is also performed to list measures that theoretically should be in place to ensure the quality of the protein drug, for example validated and protocol-based compounding in cleanroom, training and validated transports. © 2023 The Authors

  • 32.
    Matougui, Nada
    et al.
    Inserm, France.
    Boge, Lukas
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Groo, Anne-Claire
    Inserm, France.
    Umerska, Anita
    Inserm, France.
    Ringstad, Lovisa
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Bysell, Helena
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Saulnier, Patrick
    Inserm, France; CHU Angers, France.
    Lipid-based nanoformulations for peptide delivery2016In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 502, no 1-2, p. 80-97Article, review/survey (Refereed)
    Abstract [en]

    Nanoformulations have attracted a lot of attention because of their size-dependent properties. Among the array of nanoformulations, lipid nanoformulations (LNFs) have evoked increasing interest because of the advantages of their high degree of biocompatibility and versatility. The performance of lipid nanoformulations is greatly influenced by their composition and structure. Therapeutic peptides represent a growing share of the pharmaceutical market. However, the main challenge for their development into commercial products is their inherent physicochemical and biological instability. Important peptides such as insulin, calcitonin and cyclosporin A have been incorporated into LNFs. The association or encapsulation of peptides within lipid-based carriers has shown to protect the labile molecules against enzymatic degradation. This review describes strategies used for the formulation of peptides and some methods used for the assessment of association efficiency. The advantages and drawbacks of such carriers are also described.

  • 33.
    Melin, Jeanette
    et al.
    RISE Research Institutes of Sweden, Safety and Transport, Measurement Technology.
    Cano, S. J.
    Modus Outcomes, UK.
    Göschel, L.
    Charité Universitätsmedizin Berlin, Germany.
    Fillmer, A.
    PTB Physikalisch-Technische Bundesanstalt, Germany.
    Lehmann, S.
    Univ Montpellier, France.
    Hirtz, C.
    Univ Montpellier, France.
    Flöel, A.
    University Medicine Greifswald, Germany; German Center for Neurodegenerative Diseases, Germany.
    Pendrill, Leslie
    RISE Research Institutes of Sweden, Safety and Transport, Measurement Technology.
    Metrological references for person ability in memory tests2021In: Measurement: Sensors, ISSN 2665-9174, Vol. 18, article id 100289Article in journal (Refereed)
    Abstract [en]

    To ensure reliable diagnosis and treatment consistently throughout healthcare, metrological quality assurance is essential. There are, however, many observations in the social sciences and healthcare, such as the memory tests studied here, which have been ‘claimed’ to be measurements but in fact have not been fully metrologically legitimated. We have already argued in favour of extending traditional metrological underlying principles to cover social measurements, including the development of construct specification equations (CSE) considered as ‘recipes for certified reference materials (CRM)’ for traceability, analogous to CRMs in metrology in chemistry. Although the CSE approach has to date been used mostly to explain and validate test item attributes, this paper turns to focus on causal explanations of person characteristics. We describe methods and preliminary results developed in the European EMPIR NeuroMET projects, which may be used for providing quality assured measurement of disease progression and treatment benefits for patients with neurodegenerative conditions. 

  • 34.
    Melin, Jeanette
    et al.
    RISE Research Institutes of Sweden, Safety and Transport, Measurement Technology.
    Cano, Stefan
    ModusOutcomes, UK.
    Göschel, Laura
    Universitätsmedizin, Germany.
    Flöel, Agnes
    University Medicine Greifswald, Germany; German Centre for Neurodegenerative Diseases, Germany.
    Pendrill, Leslie
    RISE Research Institutes of Sweden, Safety and Transport, Measurement Technology.
    NeuroMET Memory Metric: Improving accuracy and comparability with crosswalks2023In: Alzheimer’s & Dementia: Translational Research & Clinical Interventions, E-ISSN 2352-8737, Vol. 19, no S4, article id e063924Article in journal (Refereed)
    Abstract [en]

    Background: The ability to measure, track over time, and compare memory ability for people with neurodegeneration is important. However, currently, full comparability of memory test data is limited by a lack of quality assurance of memory measurements. At AAIC 2021, we presented a preliminary item bank to assess memory, composed by selecting items from legacy tests according to metrological principles through use of the Rasch model and with item equivalence based on entropy. Method: Here, we demonstrate direct comparability of measurements generated from different tests, with the new NeuroMET Memory Metric comprising 87 selected items for task difficulty from: the Corsi Block Test, Digit Span Test, Rey’s Auditory Verbal Learning Test, Word Learning List from the CERAD test battery and the Mini Mental State Examination. Data were collected from the European EMPIR NeuroMET and the SmartAge studies recruited at Charité Hospital (Healthy controls n = 92; Subjective cognitive decline n = 160; Mild Cognitive Impairment n = 50; and Alzheimer’s Disease n = 58; age range 55-87). Results: The Rasch analysis showed well-targeted items for all participants’ abilities; good fit to the measurement model, with 83 items (95%) having fit residuals within the expected range and satisfactory unidimensionality, and item reliability of 0.96. The full item bank comprising 87 short-term memory items gave a person reliability of 0.85. Subsequently, a conversion table was created linking the raw scores from the legacy tests to the common NeuroMET Memory Metric and to individual legacy tests. Conclusion: Legacy memory tests have previously proven useful in clinical practice and research, and will continue to be used, but have to date been metrologically limited. The provided conversion table, linking these legacy memory tests to a metrologically assured scale, viz., the NeuroMET memory metric, remedies this deficiency. The NeuroMET memory metric will be included in the first ever prototype of a metrological validated app used to deliver memory tests. Clinicians and researchers will be able to select sets of items to produce data, via a scoring algorithm for transforming patient responses to measures, in a common frame of reference.

  • 35.
    Melin, Jeanette
    et al.
    RISE - Research Institutes of Sweden, Safety and Transport, Measurement Science and Technology.
    Pendrill, Leslie
    RISE - Research Institutes of Sweden, Safety and Transport, Measurement Science and Technology.
    Quality assurance of cognitive assessments and other categorical data2019Conference paper (Other academic)
    Abstract [en]

    Did you ever wonder how to account for biases such as ceiling eects in your (cognitive) data?

    Metrological quality assurance of human-based responses is in its infancy and analyzing categorial data and other human responses is challenging. However, there is a need to tackle those challenges to ensure that decisions about health care are made correctly. Quality assured comparability, interoperability and decision-making can successfully be done by applying sound metrological approaches to enable traceability as well as stressing declaration of measurement uncertainties. In the seminar, we present metrological approaches to ensure quality assurance of categorical data,such as cognitive assessments and other human-reported responses. This is followed by a hands-onworkshop where you are welcome to bring your own or freely available data for analyses.

  • 36.
    Moodie, Lindon W. K.
    et al.
    UiT The Arctic University of Norway, Norway.
    Žužek, Monika C.
    University of Ljubljana, Slovenia.
    Frangež, Robert
    University of Ljubljana, Slovenia.
    Andersen, Jeanette H.
    UiT The Arctic University of Norway, Norway.
    Hansen, Espen
    UiT The Arctic University of Norway, Norway.
    Olsen, Elisabeth K.
    UiT The Arctic University of Norway, Norway.
    Cergolj, Marija
    University of Ljubljana, Slovenia; University of Rijeka, Croatia.
    Sepčić, Kristina
    University of Ljubljana, Slovenia.
    Hansen, Kine Ø
    UiT The Arctic University of Norway, Norway.
    Svenson, Johan
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik. UiT The Arctic University of Norway, Norway.
    Synthetic analogs of stryphnusin isolated from the marine sponge: Stryphnus fortis inhibit acetylcholinesterase with no effect on muscle function or neuromuscular transmission2016In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 14, no 47, p. 11220-11229Article in journal (Refereed)
    Abstract [en]

    The marine secondary metabolite stryphnusin (1) was isolated from the boreal sponge Stryphnus fortis, collected off the Norwegian coast. Given its resemblance to other natural acetylcholinesterase antagonists, it was evaluated against electric eel acetylcholinesterase and displayed inhibitory activity. A library of twelve synthetic phenethylamine analogs, 2a-7a and 2b-7b, containing tertiary and quaternary amines respectively were synthesized to investigate the individual structural contributions to the activity. Compound 7b was the strongest competitive inhibitor of both acetylcholinesterase and butyrylcholinesterase with IC50 values of 57 and 20 μM, respectively. This inhibitory activity is one order of magnitude higher than the positive control physostigmine, and is comparable with several other marine acetylcholinesterase inhibitors. The physiological effect of compound 7b on muscle function and neuromuscular transmission was studied and revealed a selective mode of action at the investigated concentration. This data is of importance as the interference of therapeutic acetylcholinesterase inhibitors with neuromuscular transmission can be problematic and lead to unwanted side effects. The current findings also provide additional insights into the structure-activity relationship of both natural and synthetic acetylcholinesterase inhibitors.

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  • 37.
    Nadjai, Ali
    et al.
    University of Ulster, Ireland.
    Alam, Naveed
    FireSERT, Ireland.
    Charlier, Mariaon
    Arcelormittal Global RD, Luxembourg.
    Vassart, Olivier
    ArcelorMittal Inc, Luxembourg.
    Dai, Xu
    University of Edinburgh, UK; NIST, USA.
    Franssen, Jean-Marc
    Universite de Liege, Belgium.
    Sjöström, Johan
    RISE Research Institutes of Sweden, Safety and Transport, Fire and Safety.
    Travelling fire in full scale experimental building subjected to open ventilation conditions2023In: Journal of Structural Fire Engineering, ISSN 2040-2317, E-ISSN 2040-2325, Vol. 14, no 2, p. 149-166Article in journal (Refereed)
    Abstract [en]

    Purpose: In the frame of the European RFCS TRAFIR project, three large compartment fire tests involving steel structure were conducted by Ulster University, aiming at understanding in which conditions a travelling fire develops, as well as how it behaves and impacts the surrounding structure. Design/methodology/approach: During the experimental programme, the path and geometry of the travelling fire was studied and temperatures, heat fluxes and spread rates were measured. Influence of the travelling fire on the structural elements was also monitored during the travelling fire tests. Findings: This paper provides details related to the influence of travelling fires on a central structural steel column. Originality/value: The experimental data are presented in terms of the gas temperatures recorded in the test compartment near the column, as well as the temperatures recorded in the steel column at different levels. Because of the large data, only fire test one results are discussed in this paper.

  • 38.
    Nilsson, Martin
    et al.
    RISE Research Institutes of Sweden, Digital Systems, Data Science.
    Jörntell, Henrik
    Lund University, Sweden.
    Channel current fluctuations conclusively explain neuronal encoding of internal potential into spike trains2021In: Physical review. E, ISSN 2470-0045, E-ISSN 2470-0053, Vol. 103, no 2, article id 022407Article in journal (Refereed)
    Abstract [en]

    Hodgkin and Huxley's seminal neuron model describes the propagation of voltage spikes in axons, but it cannot explain certain full-neuron features crucial for understanding the neural code. We consider channel current fluctuations in a trisection of the Hodgkin-Huxley model, allowing an analytic-mechanistic explanation of these features and yielding consistently excellent matches with in vivo recordings of cerebellar Purkinje neurons, which we use as model systems. This shows that the neuronal encoding is described conclusively by a soft-thresholding function having just three parameters. © 2021 authors. Published by the American Physical Society. Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.

  • 39.
    Nilsson, Martin
    et al.
    RISE Research Institutes of Sweden, Digital Systems, Data Science.
    Jörntell, Henrik
    Lund University, Sweden.
    What Neurons do – and don’t do2021In: Ercim News, Vol. 25, p. 37-38Article in journal (Other academic)
    Abstract [en]

    Biology-inspired computing is often based on spiking networks, but can we improve efficiency by going to higher levels of abstraction? To do this, we need to explain the precise meaning of the spike trains that biological neurons use for mutual communication. In a cooperation between RISE and Lund University, we found a spectacular match between a mechanistic, theoretical model having only three parameters on the one hand, and in vivo neuron recordings on the other, providing a clear picture of exactly what biological neurons “do”, i.e., communicate to each other.

  • 40.
    Norbäck, D.
    et al.
    Uppsala University, Sweden.
    Hashim, J. H.
    United Nations University-International Institute for Global Health, Malaysia; National University of Malaysia, Malaysia.
    Cai, G. -H
    Uppsala University, Sweden.
    Hashim, Z.
    Universiti Putra Malaysia, Malaysia.
    Ali, F.
    Johor Bahru, Malaysia.
    Bloom, Erica
    RISE Research Institutes of Sweden, Built Environment, Building and Real Estate. Lund University, Sweden; IVL, Sweden.
    Larsson, L.
    Lund University, Sweden.
    Rhinitis, ocular, throat and dermal symptoms, headache and tiredness among students in schools from johor bahru, Malaysia: Associations with fungal DNA and mycotoxins in classroom dust2016In: PLoS ONE, Vol. 11, no 2Article in journal (Refereed)
  • 41.
    Nyström, Lina
    et al.
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Mira, Isabel
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Benjamins, Jan-Willem
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Gopaul, Sashi
    AstraZeneca, Sweden.
    Granfeldt, Andreas
    AstraZeneca, Sweden.
    Abrahamsson, Bertil
    AstraZeneca, Sweden.
    von Corswant, Christian
    AstraZeneca, Sweden.
    Abrahmsén-Alami, Susanna
    AstraZeneca, Sweden.
    In Vitro and In Vivo Performance of Pickering Emulsion-Based Powders of Omega-3 Polyunsaturated Fatty Acids2023In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392Article in journal (Refereed)
    Abstract [en]

    Omega-3 polyunsaturated fatty acids (n-3 PUFA) are essential nutrients for human health and have been linked to a variety of health benefits, including reducing the risk of cardiovascular diseases. In this paper, a spray-dried powder formulation based on Pickering emulsions stabilized with cellulose nanocrystals (CNC) and hydroxypropyl methylcellulose (HPMC) has been developed. The formulation was compared in vitro and in vivo to reference emulsions (conventional Self-Emulsifying Drug Delivery System, SEDDS) to formulate n-3 PUFA pharmaceutical products, specifically in free fatty acid form. The results of in vivo studies performed in fasted dogs showed that Pickering emulsions reconstituted from powders are freely available (fast absorption) with a similar level of bioavailability as reference emulsions. In the studies performed with dogs in the fed state, the higher bioavailability combined with slower absorption observed for the Pickering emulsion, compared to the reference, was proposed to be the result of the protection of the n-3 PUFAs (in free fatty acid form) against oxidation in the stomach by the solid particles stabilizing the emulsion. This observation was supported by promising results from short-term studies of chemical stability of powders with n-3 PUFA loads as high as 0.8 g oil/g powder that easily regain the original emulsion drop sizes upon reconstitution. The present work has shown that Pickering emulsions may offer a promising strategy for improving the bioavailability and stability as well as providing an opportunity to produce environmentally friendly (surfactant free) and patient-acceptable solid oral dosage forms of n-3 PUFA in the free fatty acid form.

  • 42.
    Nyström, Lina
    et al.
    Uppsala University, Sweden.
    Nordström, Randi
    Uppsala University, Sweden.
    Bramhill, Jane
    University of Manchester, UK.
    Saunders, Brian R.
    University of Manchester, UK.
    Álvarez-Asencio, Rubén
    KTH Royal Institute of Technology, Sweden; IMDEA Nanoscience, Spain.
    Rutland, Mark W.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science. KTH Royal Institute of Technology, Sweden.
    Malmsten, Martin
    Uppsala University, Sweden.
    Factors affecting peptide interactions with surface-bound microgels2016In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 17, no 2, p. 669-678Article in journal (Refereed)
    Abstract [en]

    Effects of electrostatics and peptide size on peptide interactions with surface-bound microgels were investigated with ellipsometry, confocal microscopy, and atomic force microscopy (AFM). Results show that binding of cationic poly-l-lysine (pLys) to anionic, covalently immobilized, poly(ethyl acrylate-co-methacrylic acid) microgels increased with increasing peptide net charge and microgel charge density. Furthermore, peptide release was facilitated by decreasing either microgel or peptide charge density. Analogously, increasing ionic strength facilitated peptide release for short peptides. As a result of peptide binding, the surface-bound microgels displayed pronounced deswelling and increased mechanical rigidity, the latter quantified by quantitative nanomechanical mapping. While short pLys was found to penetrate the entire microgel network and to result in almost complete charge neutralization, larger peptides were partially excluded from the microgel network, forming an outer peptide layer on the microgels. As a result of this difference, microgel flattening was more influenced by the lower Mw peptide than the higher. Peptide-induced deswelling was found to be lower for higher Mw pLys, the latter effect not observed for the corresponding microgels in the dispersed state. While the effects of electrostatics on peptide loading and release were similar to those observed for dispersed microgels, there were thus considerable effects of the underlying surface on peptide-induced microgel deswelling, which need to be considered in the design of surface-bound microgels as carriers of peptide loads, for example, in drug delivery or in functionalized biomaterials.

  • 43.
    Olsen, Elisabeth K.
    et al.
    UiT The Arctic University of Norway, Norway.
    Hansen, Espen
    UiT The Arctic University of Norway, Norway.
    Moodie, Lindon W. K.
    University of Umeå, Sweden.
    Isaksson, Johan
    UiT The Arctic University of Norway, Norway.
    Sepčić, Kristina
    University of Ljubljana, Slovenia.
    Cergolj, Marija
    University of Ljubljana, Slovenia; University of Rijeka, Croatia.
    Svenson, Johan
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik.
    Andersen, Jeanette H.
    UiT The Arctic University of Norway, Norway.
    Marine AChE inhibitors isolated from Geodia barretti: Natural compounds and their synthetic analogs2016In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 14, no 5, p. 1629-1640Article in journal (Refereed)
    Abstract [en]

    Barettin, 8,9-dihydrobarettin, bromoconicamin and a novel brominated marine indole were isolated from the boreal sponge Geodia barretti collected off the Norwegian coast. The compounds were evaluated as inhibitors of electric eel acetylcholinesterase. Barettin and 8,9-dihydrobarettin displayed significant inhibition of the enzyme, with inhibition constants (Ki) of 29 and 19 μM respectively towards acetylcholinesterase via a reversible noncompetitive mechanism. These activities are comparable to those of several other natural acetylcholinesterase inhibitors of marine origin. Bromoconicamin was less potent against acetylcholinesterase, and the novel compound was inactive. Based on the inhibitory activity, a library of 22 simplified synthetic analogs was designed and prepared to probe the role of the brominated indole, common to all the isolated compounds. From the structure-activity investigation it was shown that the brominated indole motif is not sufficient to generate a high acetylcholinesterase inhibitory activity, even when combined with natural cationic ligands for the acetylcholinesterase active site. The four natural compounds were also analysed for their butyrylcholinesterase inhibitory activity in addition and shown to display comparable activities. The study illustrates how both barettin and 8,9-dihydrobarettin display additional bioactivities which may help to explain their biological role in the producing organism. The findings also provide new insights into the structure-activity relationship of both natural and synthetic acetylcholinesterase inhibitors.

  • 44.
    Peitzsch, M.
    et al.
    Lund University, Sweden; Technical University Dresden, Germany.
    Bloom, Erica
    IVL, Sweden.
    Haase, R.
    Technical University Dresden, Germany.
    Must, A.
    IVL, Sweden.
    Larsson, L.
    Lund University, Sweden.
    Remediation of mould damaged building materials - Efficiency of a broad spectrum of treatments2012In: Journal of Environmental Monitoring, ISSN 1464-0325, E-ISSN 1464-0333, Vol. 14, no 3, p. 908-915Article in journal (Refereed)
    Abstract [en]

    We compared the efficiency of some commercially available products and methods used for remediation of mould-contaminated building materials. Samples of gypsum board and pinewood were artificially contaminated with toxin-producing isolates of Stachybotrys chartarum and Aspergillus versicolor, respectively, then, ten different remediation treatments were applied according to the manufacturers’ instructions. Microbial and chemical analyses of the infested materials were carried out both immediately before and after treatment, after six weeks of drying at room temperature, and after another six weeks of remoistening. The aim of the study was to determine whether the investigated methods could inhibit the mould growth and destroy some selected mycotoxins produced by the moulds. None of the decontamination methods tested could completely eliminate viable moulds. Some methods, especially boron based chemicals, ammonium based chemicals, and oxidation reduced the contents of mycotoxins produced by S. chartarum (satratoxin G and H, verrucarol), whereas the one which uses an ammonium based chemical reduced the amount of sterigmatocystin produced by A. versicolor with statistical significance. No remediation treatment eliminated all the toxins from the damaged materials. These results emphasize the importance to work preventively with moisture safety throughout the construction processes and management to prevent mould growth on building materials.

  • 45.
    Pendrill, Leslie
    RISE - Research Institutes of Sweden, Safety and Transport, Measurement Science and Technology.
    Assuring measurement quality in person-centred healthcare2018In: Measurement science and technology, ISSN 0957-0233, E-ISSN 1361-6501, Vol. 29, no 3, p. 034003-Article in journal (Refereed)
    Abstract [en]

    Is it realistic to aspire to the same kind of quality-assurance of measurement in person-centred care, currently being implemented in healthcare globally, as is established in the physical sciences and engineering? Ensuring metrological comparability (‘traceability’) and reliably declaring measurement uncertainty when assessing patient ability or increased social capital are however challenging for subjective measurements often characterised by large dispersion. Drawing simple analogies between ‘instruments’ in the social sciences – questionnaires, ability tests, etc.–  and  engineering instruments such as thermometers does not go far enough. A possible way forward apparently equally applicable to both physical and social measurement, seems to be to model inferences in terms performance metrics of a measurement system. Person-centred care needs person-centred measurement and a full picture of the measurement process when Man acts as a measurement instrument is given in the present paper. This complements previous work by presenting the process, step by step, from the observed indication (e.g. probability of success, Psuccess, of achieving atask), through restitution with Rasch Measurement Theory, to the measurand (e.g. task difficulty). Rasch invariant measure theory can yield quantities –‘latent’ (or ‘explanatory’) variables such as task challenge or person ability – with characteristics akin to those of physical quantities. Metrological references for comparability via traceability and reliable estimates ofuncertainty and decision risks are then in reach even for perceptive measurements (and other qualitative properties). As a case study, the person-centred measurement of cognitive ability is examined, as part of the EUproject EMPIR 15HLT04 NeuroMet, for Alzheimer’s, where better analysis of correlations with brain atrophy is enabled thanks to the Rasch metrological approach.

  • 46.
    Pendrill, Leslie
    RISE - Research Institutes of Sweden, Safety and Transport, Measurement Science and Technology.
    Metrological qualityassurance in person-centred healthcare and other qualitative observations2017In: Abteilung 8: Medizinphysik und metrologische Informationstechnik, Berlin, 2017Conference paper (Other academic)
    Abstract [en]

    Measurements with categorical data – produced with ‘instruments’ such as questionnaires, ability tests, – in education, healthcare and so on, need metrological quality assurance. A patient expects that the quality of care will be comparable wherever and whenever care is provided, but metrological quality assurance has yet to be developed in many cases. When seeking an increased stringency in measurement where human perception is a key factor, ensuring metrological comparability (‘traceability’) and reliably declaring measurement uncertainty when assessing patient ability, service satisfaction or material hardness are challenging. Subjective measurements are often characterised by large dispersion; the usual tools of statistics do not always work on the categorical and ordinal scales typical of such measurements; and an independent objective reality in what is being measured might be questioned. Drawing simple analogies between engineering instruments such as thermometers and social instruments such as questionnaires merely in terms of measurement error does not go far enough when attempting to introduce metrology to qualitative observations (examinations, assessments, opinions). Modelling inferences of a measurement system where the instrument is a human being, and where the output of the instrument in response to probing an object (‘entity’) is a performance metric, i.e., how well the set-up performs the assessment, does appear to be a way forward. Be it decision risks arising from measurement uncertainty or responses to a cognitive test in a clinic for Alzheimer patients, a psychometric, generalised linear model can yield quantities, ‘latent’ (or ‘explanatory’) variables, – task challenge or person ability – which seem to possess quantitative characteristics akin to those of physical quantities. Metrological references for comparability via traceability and reliable estimates of uncertainty and decision risks are then in reach even for perceptive measurements. Metrological quality assurance in person-centred healthcare is being developed for sufferers in cases such as Myotonic Dystrophy and Alzheimer’s disease, as studied in the EMPIR 15HLT04 NeuroMet project

  • 47.
    Quaglia, Milena
    et al.
    LGC, UK.
    Bellotti, Vittorio
    University College London, UK.
    Cano, Stefan
    Modus Outcomes, UK.
    Cyrar, Adam
    LGC, UK.
    Deane, Katherine
    University East Anglia, UK.
    Divieto, Carla
    Istituto Nazionale di Ricerca Metrologica, Italy.
    Fillmer, Ariane
    PTB Physikalisch-Technische Bundesanstalt, Germany.
    Giangrande, Chiara
    Laboratoire National de Métrologie et d'Essais, France.
    Köbe, Theresa
    Humboldt-Universität zu Berlin, Germany; Berlin Institute of Health, Germany.
    Lehmann, Sylvain
    CHU Montpellier, France.
    Melin, Jeanette
    RISE - Research Institutes of Sweden (2017-2019), Safety and Transport, Measurement Science and Technology.
    Pang, Susan
    LGC, UK.
    Parkes, Helen
    LGC, UK.
    Pendrill, Leslie
    RISE - Research Institutes of Sweden (2017-2019), Safety and Transport, Measurement Science and Technology.
    Better Measurement for Improved Diagnosis and Management of Alzheimer's Disease: Update on the Empir Neuromet Project2018In: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 14, p. P759-P760, article id 7Article in journal (Other academic)
    Abstract [en]

    The development of novel therapies for Alzheimer’s Disease (AD) is constrained by the lack of available methods for preclinical diagnosis, despite extensive research on biomarker identification. Here, we present an update of progress from EMPIR NeuroMET, a project combining diverse expertise from five National Measurement Institutes (NMIs), with clinicians and academics, to overcome limitations in measurement methods in neurodegenerative disease diagnosis and treatment.

  • 48.
    Rao, Komal Umashankar
    et al.
    Lund University, Sweden.
    Henderson, Domhnall Iain
    Lund University, Sweden.
    Krishnan, Nitya
    Imperial College, UK.
    Puthia, Manoj
    Lund University, Sweden.
    Glegola-Madejska, Izabela
    Imperial College, UK.
    Brive, Lena
    RISE Research Institutes of Sweden, Materials and Production, Manufacturing Processes.
    Bjarnemark, Fanny
    RISE Research Institutes of Sweden, Materials and Production, Chemistry, Biomaterials and Textiles.
    Millqvist-Fureby, Anna
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Hjort, Karin
    Uppsala University, Sweden.
    Andersson, Dan I.
    Uppsala University, Sweden.
    Tenland, Erik
    Lund University, Sweden.
    Sturegård, Erik
    Lund University, Sweden.
    Robertson, Brian D.
    Imperial College, UK.
    Godaly, Gabriela
    Lund University, Sweden.
    A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, article id 4201Article in journal (Refereed)
    Abstract [en]

    Alternative ways to prevent and treat infectious diseases are needed. Previously, we identified a fungal peptide, NZX, that was comparable to rifampicin in lowering M. tuberculosis load in a murine tuberculosis (TB) infection model. Here we assessed the potential synergy between this cationic host defence peptide (CHDP) and the current TB drugs and analysed its pharmacokinetics. We found additive effect of this peptide with isoniazid and ethambutol and confirmed these results with ethambutol in a murine TB-model. In vivo, the peptide remained stable in circulation and preserved lung structure better than ethambutol alone. Antibiotic resistance studies did not induce mutants with reduced susceptibility to the peptide. We further observed that this peptide was effective against nontuberculous mycobacteria (NTM), such as M. avium and M. abscessus, and several Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. In conclusion, the presented data supports a role for this CHDP in the treatment of drug resistant organisms.

  • 49.
    Rinwa, Vihbu
    et al.
    RISE - Research Institutes of Sweden, Bioscience and Materials, Surface, Process and Formulation.
    Schipper, Nicolaas
    RISE - Research Institutes of Sweden, Bioscience and Materials, Surface, Process and Formulation.
    Bohlin, Martin
    RISE - Research Institutes of Sweden, Bioscience and Materials, Surface, Process and Formulation.
    Warpman Berglund, Ulrika
    KI Karolinska Institute, Sweden.
    Scobie, Martin
    KI Karolinska Institute, Sweden.
    Helleday, Thomas
    KI Karolinska Institute, Sweden.
    Effect of chloride ion on solubility and dissolution of a basic drug and salt form for oral delivery2018Conference paper (Other academic)
    Abstract [en]

    Introduction:

    Chloride ions are the predominant anionic counter-ion present in vivo (intestine/ jejunum: 0.13M and stomach: 0.10M), significantly effecting solubility and dissolution of drugs for oral absorption1. Our group has recently discovered a novel small molecule, with good permeability but low aqueous solubility potentially limiting exposure after oral administration. It is a basic compound (pKa- 6-7) and provides opportunities to develop salt exploiting different counter-ions. Solubility is not only dependent on the ionization of the weak acid or weak base itself but also on the solubility of the counter ion pairs. Counter ion exchanges between salt forms or formation of hydrates is well known to occur in the gastrointestinal environment. If this happens, then formation of less soluble species can lead to in vivo precipitation of the drug.

  • 50.
    Rosendahl, Jennifer
    et al.
    RISE Research Institutes of Sweden, Materials and Production, Chemistry, Biomaterials and Textiles.
    Svanström, Andreas
    University of Gothenburg, Sweden.
    Berglin, Mattias
    RISE Research Institutes of Sweden, Materials and Production, Chemistry, Biomaterials and Textiles.
    Petronis, Sarunas
    RISE Research Institutes of Sweden, Materials and Production, Chemistry, Biomaterials and Textiles.
    Bogestål, Yalda
    RISE Research Institutes of Sweden, Materials and Production, Chemistry, Biomaterials and Textiles.
    Stenlund, Patrik
    RISE Research Institutes of Sweden, Materials and Production, Chemistry, Biomaterials and Textiles.
    Standoft, Simon
    RISE Research Institutes of Sweden, Materials and Production, Chemistry, Biomaterials and Textiles.
    Ståhlberg, Anders
    University of Gothenburg, Sweden; Sahlgrenska University Hospital, Sweden.
    Landberg, Göran
    University of Gothenburg, Sweden; Sahlgrenska University Hospital, Sweden.
    Chinga-Carrasco, Gary
    RISE Research Institutes of Sweden, Bioeconomy and Health, Material and Surface Design. University of Gothenburg, Sweden.
    Håkansson, Joakim
    University of Gothenburg, Sweden.
    3D Printed Nanocellulose Scaffolds as a Cancer Cell Culture Model System2021In: Bioengineering, E-ISSN 2306-5354, Vol. 8, no 7, article id 97Article in journal (Refereed)
    Abstract [en]

    Current conventional cancer drug screening models based on two-dimensional (2D) cell culture have several flaws and there is a large need of more in vivo mimicking preclinical drug screening platforms. The microenvironment is crucial for the cells to adapt relevant in vivo characteristics and here we introduce a new cell culture system based on three-dimensional (3D) printed scaffolds using cellulose nanofibrils (CNF) pre-treated with 2,2,6,6-tetramethylpyperidine-1-oxyl (TEMPO) as the structural material component. Breast cancer cell lines, MCF7 and MDA-MB-231, were cultured in 3D TEMPO-CNF scaffolds and were shown by scanning electron microscopy (SEM) and histochemistry to grow in multiple layers as a heterogenous cell population with different morphologies, contrasting 2D cultured mono-layered cells with a morphologically homogenous cell population. Gene expression analysis demonstrated that 3D TEMPO-CNF scaffolds induced elevation of the stemness marker CD44 and the migration markers VIM and SNAI1 in MCF7 cells relative to 2D control. T47D cells confirmed the increased level of the stemness marker CD44 and migration marker VIM which was further supported by increased capacity of holoclone formation for 3D cultured cells. Therefore, TEMPO-CNF was shown to represent a promising material for 3D cell culture model systems for cancer cell applications such as drug screening.

12 1 - 50 of 66
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