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1.	Fonzo, Vito Di, et al. (författare) Multi-sensor system for non-invasive online analysis and control in bioreactors 2013 Ingår i: BioMicroWorld 2013, Madrid, Spain, October 2-4. Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Sökbart abstract via länken: http://www.formatex.info/biomicroworld2013/acceptedabstracts.php
2.	Sukhovey, Yurij G., et al. (författare) Difference between the biologic and chronologic age as an individualized indicator for the skin care intensity selection : skin topography and immune system state studies, parameter correlations with age difference 2019 Ingår i: Biomedical Dermatology. - : Springer Nature. - 2398-8460. ; 3 Tidskriftsartikel (refereegranskat)abstract Background: Present research addresses the issue of skin aging and corresponding skin treatment individualization. Particular research question was on the developing of simplified criterion supporting patient-specific decision on the necessity and intensity of skin treatment. Basing on the published results and a wide pool of experimental data, we have formulated a hypothesis that a difference between biologic and chronologic age can be used as an express criterion of skin aging.Methods: In present paper, we report the results of studies with 80 volunteers between 15 and 65 years of age, linking parameters reflecting immune state, skin state, and topography to the difference between biologic and chronologic age. Facial skin topography, skin moisture, sebum level, and skin elasticity were studied using commercial devices. Blood immunology studies were performed using venous blood samples. Correlations between all measured parameters and age difference were calculated. Also, cross correlations between skin cell profile and blood immune profile parameters, and skin roughness parameters were calculated.Results: Age dependencies of the blood immunological parameters on the biologic and chronologic age difference are less pronounced as compared to the changes in skin cell profile parameters. However, the changes in the tendencies when biologic age becomes equal to chronologic one are visible for all studied parameters.All measured skin roughness parameters show correlations with age difference, but average skin roughness and depth of the deepest profile valley have the largest correlation coefficient values. Many of the measured skin cell profile and blood immunology parameters show strong correlations with average skin roughness and deepest profile valley, with some of the coefficients exceeding 0.5–0.6.Conclusions: Basing on own experiments and published research results, it is possible to suggest using the difference between calculated biologic age and chronologic age as an individualized criterion supporting decisions on skin treatment strategy. Further research involving larger numbers of participants and aiming on optimizing the expressions for calculating biologic age could lead to reliable and easily available express criterion supporting the decision making for an individualized skin treatment.
3.	Lind-Halldén, Christina, et al. (författare) Genetic variation in the syntaxin-binding protein STXBP5 in type 1 von Willebrand disease patients 2018 Ingår i: Thrombosis and haemostasis. - 2567-689X. ; 118:8, s. 1382-1389 Tidskriftsartikel (refereegranskat)abstract von Willebrand factor (VWF) levels in healthy individuals and in patients with type 1 von Willebrand disease (VWD) are influenced by genetic variation in several genes, for example, VWF, ABO and STXBP5. Here, we comprehensively screen for STXBP5 variants and investigate their association with type 1 VWD in Swedish patients and controls. The coding region of the STXBP5 gene was re-sequenced in 107 type 1 VWD patients and the detected variants were genotyped in the type 1 VWD population and a Swedish control population (464 individuals). The functional effects of missense alleles were predicted in silico and the pattern of genetic variation in STXBP5 was analysed. Re-sequencing of 107 type 1 VWD patients identified three missense and three synonymous variants in the coding sequence of STXBP5. The low-frequency missense variants rs144099092 (0.005) and rs148830578 (0.029) were predicted to be damaging, but were not accumulated in patients. No other rare candidate mutations were detected. STXBP5 showed a high level of linkage disequilibrium and a low overall nucleotide diversity of π = 3.2 × 10-4 indicating intolerance to variants affecting protein function. Three previously type 1 VWD-associated single nucleotide polymorphisms were located on one haplotype that showed an increased frequency in patients versus controls. No differences in messenger ribonucleic acid abundance among haplotypes could be found using Genotype-Tissue Expression project data. In conclusion, a haplotype containing the STXBP5 Asn436Ser (rs1039084) mutation is associated with type 1 VWD and no rare STXBP5 mutations contribute to type 1 VWD in the Swedish population.
4.	André, Oscar (författare) Data-driven microscopy: placing high-fidelity data in a population-wide context 2023 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Mikroskopi är idag ett fundamentalt verktyg inom forskning, där det tillåter oss att skåda in och utforska våra prover i hög detalj. Mycket utav utvecklingen av nya mikroskopimetoder har strävat efter att öka den detaljnivå vi kan uppnå. Samtidigt har utvecklingen inom hårdvara, med tillgång till bättre och mer kraftfulla instrument, lett till utveckligen av metoder där fokuset är att studera en hel population av celler. Till skillnad från när vi studerar ett fåtal celler i hög detalj, tillåter det oss att sätta perspektiv på det vi ser. Det ger oss en förmåga att säga vad det normala beteendet som man kan förvänta sig är, och vilka celler som sticker ut i en population. Med andra ord, vad som är intressant.Samtidigt finns det ett stort intresse av att veta hur varje individuell cell beter sig. Varje cell är, precis som oss människor, unik. De har olika historia, olika ålder och befinner sig i olika tillstånd. Precis som våra celler i kroppen är unika, är även de cellerna som kan orsaka sjukdom unika. För att förstå varför vissa personer är mer känsliga mot sjukdom, och hur en infektion svarar på våra behandlingar behövs en förståelse och an förmåga att studera celler på individuell nivå, samtidigt som vi bibehåller ett perspektiv utifrån populations-nivå.Denna brist på perspektiv har länge varit ett problem inom mikroskopi. Den vanliga lösningen på detta problem är att vi, som människor, kan tolka en bild och peka på vad det är som är intressant eller inte. Vi är, trots allt, extremt duktiga på att tolka visuell information. Men detta är inte en helt felfri lösning. Som människor kan vi vara relativt okonsekventa, vi tolkar oftast utifrån hur vi vill att datan ser ut. Med andra ord, vi saknar förmågan att vara objektiva i vår metodik för att samla in bilder i hög detalj.Min avhandling har till stor del handlat om att utveckla ett verktyg som tillåter oss att sätta perspektiv på det vi studerar med mikroskopi. Detta har lett till Arbete 1, där vi presenterar en allmän strategi (data-styrd mikroskopi) för hur vi kan arbeta med mikroskopi för att samla in data på en hel population, samtidigt som vi kan samla in data med hög detalj på relevanta fynd i populationen. Vi presenterar även här en teknisk lösning, och utför metoden i tre olika scenarion: ett för att studera en population av celler mer allmänt, ett för att fånga det ögonblick som bakterier infekterar mänskliga celler, och ett där vi studerar och fångar in data på relevanta (från ett populations-kontext) cancerceller och följer dem över tid. Denna metod tillåter oss att samla in data i hög detalj på ett objektivt sätt, och att sätta perspektiv på det vi studerar.I Arbete 2 har vi vidare utvecklat på vår metod, där vi försöker lösa problemet att hitta en och samma cell i flera olika mikroskop. Eftersom vi, genom mikroskopi, jobbar på en så ofantligt liten skala, är det oftast väldigt svårt att orientera sig och hitta rätt inom ett prov. Det är lite som att spela På spåret och gissa vart man är, fast utan alla ledtrådar man får på varje nivå. Eftersom vi har tillgång till data på en hel population, så utgick vi från att det borde finnas samband mellan celler och deras grannar i ett prov som är unika för just dem. Genom att använda sig av dessa unika samband kom vi fram med en lösning där vi snabbt kan kalibrera ett prov på ett nytt mikroskop. Det öppnar dörrarna för oss forskare att återanvända prov, att lättare justera provet med nya markörer (för det vi vill visualisera inom cellerna), och att kunna tolka ett prov med data insamlat från flera system.COVID-19 pandemin var en stor omställning för samhället och vården. Likväl var det en stor omställning för många forskningslabb, där en kapplöpning startade för att så snabbt som möjligt förstå sig på hur viruset fungerar och hur vårt immunförsvar svarar på dess infektion. Det var i detta kontext som mitt tredje arbete utfördes. Genom den erfarenhet jag samlat på mig inom mikroskopi och att analysera bilder på stora dataset, bidrog jag med hjälp för att studera hur framtagna antikroppar kan förhindra bindningen av virus-lika partiklar till celler. Antikroppar är ett protein som immunförsvaret producerar i respons mot en patogen. En bättre förståelse kring hur antikroppar verkar, och vad skillnaden mellan en bra och en dålig antikropp är kan leda till framtagningen av bättre vaccin-program och behandlingar inom sjukvården.I Arbete 4 medverkade jag i ett arbete där bakterien Streptococcus pyogenes var i fokus. S. pyogenes enda värd är människor, och ansvarar för över 600 miljoner infektionsfall per år globalt. På bakteriens yta dominerar ett protein, M-proteinet, ett multi-funktionellt protein som bakterien (bland annat) använder sig för att binda till ytor och förhindra immunförsvarets förmåga att göra sig av med bakterien. I arbetet upptäckte vi att fibronektin binder till bakterien (specifikt M-proteinet) olika mycket beroende på mängden antikroppar som finns i miljön. Fibronektin är ett protein som vi människor producerar, och bidrar (bland annat) till att skapa den miljön som celler befinner sig i. Mängden fibronektin varierar beroende på var i kroppen man kollar. Till exempel, i saliv har du en relativt låg mängd fibronektin jämfört med i blodet. Detta ledde till hypotesen att bakterien är special-anpassad för olika miljöer i dess förmåga att undkomma immunförsvaret. En bättre förståelse kring hur bakterien är anpassad till våra olika miljöer och dess infektionsförlopp kan leda till bättre och mer anpassade behandlingar inom sjukvården.
5.	Arfvidsson, Berndt, et al. (författare) S100B concentrations increase perioperatively in jugular vein blood despite limited metabolic and inflammatory response to clinically uneventful carotid endarterectomy 2015 Ingår i: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter GmbH. - 1434-6621 .- 1437-4331. ; 53:1, s. 111-117 Tidskriftsartikel (refereegranskat)abstract Background: Our aim was to test the hypothesis that metabolic and inflammatory responses of the brain perioperatively during carotid endarterectomy (CEA) might affect blood brain barrier (BBB) integrity.Methods: Twenty patients with >70% stenosis of internal carotid artery (ICA) were prospectively included. Surgery was performed under general anaesthesia. Blood was sampled from ipsilateral internal jugular vein and radial artery: just before, during, and after ICA clamping S100B protein, glucose, lactate, 20 amino acids, and key cytokines were analysed.Results: Jugular vein S100B increased during clamping and reperfusion, while a marginal systemic increase was recorded, unrelated to stump pressure during clamping. Glucose increased during clamping in jugular vein blood and even more systemically, while jugular lactate values were higher than systemic values initially. Most amino acids did not differ significantly between jugular vein and systemic levels: glutamic acid and aspartic acid decreased during surgery while asparagine increased. Jugular vein interleukin (IL)-6 showed a transient non-significant increase during clamping and decreased systemically. IL-8 and IL-10 increased over time.Conclusions: Rising jugular vein S100B concentrations indicated reduced BBB integrity, and marginal secondary increase of S100B systemically. Limited ischaemic effects on the brain during cross-clamping, unrelated to S100B concentrations, were confirmed by lower brain glucose levels and higher lactate levels than in systemic blood. The lack of increased jugular vein glutamic acid disproves any major ischaemic brain injury following CEA. The inflammatory response was limited, did not differ greatly between jugular and systemic blood, and was unrelated to S100B.
6.	Cavallaro, Sara, 1992- (författare) Development of Techniques for Characterization, Detection and Protein Profiling of Extracellular Vesicles 2021 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Nanosized extracellular vesicles (EVs, ∼30-2000 nm) have emerged as important mediators of intercellular communication, offering opportunities for both diagnostics and therapeutics. In particular, small EVs generated from the endolysosomal pathway (∼30-150 nm), referred to as exosomes, have attracted interest as a suitable biomarker for cancer diagnostics and treatment monitoring based on minimally invasive liquid biopsies. This is because exosomes carry valuable biological information (proteins, lipids, genetic material, etc.) reflecting their cells of origin. Using EVs as biomarkers or drug delivery agents in clinical applications requires a full understanding of their cellular origin, functions, and biological relevance. However, due to their small size and very high heterogeneity in molecular and physical features, the analysis of these vesicles is challenged by the limited detection ranges and/or accuracy of the currently available techniques. To overcome some of these challenges, this thesis focuses on developing different techniques for characterization, detection and protein profiling of EVs at both bulk and single particle levels. Specifically, the three methods investigated are scanning electron microscopy, electrokinetic sensing, and combined fluorescence - atomic force microscopy. First, a protocol for scanning electron microscopy imaging of EVs was optimized to improve the throughput and image quality of the method while preserving the shape of the vesicles. Application of the developed protocol for analysis of EVs from human serum showed the possibility to use scanning electron microscopy for morphological analysis and high-resolution size-based profiling of EVs over their entire size range. Comparison with nanoparticle tracking analysis, a commonly used technique for EV size estimation, showed a superior sensitivity of scanning electron microscopy for particles smaller than 70-80 nm. Moreover, the study showed process steps that can generate artifacts resembling sEVs and ways to minimize them. Secondly, a novel label-free electrokinetic sensor based on streaming current was developed, optimized and multiplexed for EV protein analysis at a bulk level. Using multiple microcapillary sensors functionalized with antibodies, the method showed the capacity for multiplexed detection of different surface markers on small EVs from non-small-cell lung cancer cells. The device performance in the multichannel configuration remained similar to the single-channel one in terms of noise, detection sensitivity, and reproducibility. The application of the technique for analysis of EVs isolated from lung cancer patients with different genomic alterations and after different applied treatments demonstrated the prospect of using EVs from liquid biopsies as a source of biomarker for cancer monitoring. Moreover, the results held promise for the application of the developed method in clinical settings. Finally, to increase the understanding of EV subpopulations and heterogeneity, a platform combining fluorescence and atomic force microscopy was developed for multiparametric analysis of EVs at a single particle level. The use of a precise spot identification approach and an efficient vesicle capture protocol allowed to study and correlate for the first time the membrane protein composition, size and mechanical properties (Young modulus) on individual small EVs. The application of the technique to vesicles isolated from different cell lines identified both common and cell line-specific EV subpopulations bearing distinct distributions of the analyzed parameters. For example, a sEV population co-expressing all the three analyzed proteins in relatively high abundance, yet having average diameters of <100 nm and relatively low Young moduli was found in all cell lines. The obtained results highlighted the possibility of using the developed platform to help decipher unsolved questions regarding EV biology.
7.	Chantzi, Efthymia, et al. (författare) COMBSecretomics : a pragmatic methodological framework for higher-order drug combination analysis using secretomics 2020 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:5 Tidskriftsartikel (refereegranskat)abstract Multi drug treatments are increasingly used in the clinic to combat complex and co-occurring diseases. However, most drug combination discovery efforts today are mainly focused on anticancer therapy and rarely examine the potential of using more than two drugs simultaneously. Moreover, there is currently no reported methodology for performing second- and higher-order drug combination analysis of secretomic patterns, meaning protein concentration profiles released by the cells.Here, we introduce COMBSecretomics (https://github.com/EffieChantzi/COMBSecretomics.git), the first pragmatic methodological framework designed to search exhaustively for second- and higher-order mixtures of candidate treatments that can modify, or even reverse malfunctioning secretomic patterns of human cells. This framework comes with two novel model-free combination analysis methods; a tailor-made generalization of the highest single agent principle and a data mining approach based on top-down hierarchical clustering. Quality control procedures to eliminate outliers and non-parametric statistics to quantify uncertainty in the results obtained are also included. COMBSecretomics is based on a standardized reproducible format and could be employed with any experimental platform that provides the required protein release data. Its practical use and functionality are demonstrated by means of a proof-of-principle pharmacological study related to cartilage degradation.COMBSecretomics is the first methodological framework reported to enable secretome-related second- and higher-order drug combination analysis. It could be used in drug discovery and development projects, clinical practice, as well as basic biological understanding of the largely unexplored changes in cell-cell communication that occurs due to disease and/or associated pharmacological treatment conditions.
8.	Chantzi, Efthymia, et al. (författare) Exhaustive in vitro evaluation of the 9-drug cocktail CUSP9 for treatment of glioblastoma using COMBImageDL Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. Tidskriftsartikel (refereegranskat)abstract The CUSP9 protocol (aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, quetiapine, sertraline) is currently undergoing a clinical trial as add-on treatment to standard-of-care temozolomide for recurrent glioblastoma. Although the theoretical repurposing rationale of this 9-drug cocktail is well defined, there is no in vitro experimental data yet supporting its superiority over all its plausible subsets. Such an exhaustive in vitro evaluation may provide preliminary evidence of whether only a fraction of all 9 drugs is needed to achieve an equivalent or even higher effect. Such information could be further used to guide and optimize individualized glioblastoma therapy selection both in terms of efficacy and adverse effects.Here, we employed COMBImageDL, a deep learning improved version of our recently developed COMBImage2 framework, to design, perform and analyze an exhaustive in vitro experiment of the CUSP9 protocol. More specifically, all 511 plausible subsets were evaluated as add-on treatment to temozolomide on a drug resistant glioblastoma cell line (M059K), by combining endpoint cell viability analysis and quantitative live-cell imaging. The experiment was performed in quadruplicate (eight 384-well plates, > 100GB of image data). Fixed clinically achievable concentrations were used for all drugs.Our results suggest that only disulfiram from the CUSP9 cocktail is required, together with temozolomide, in order to induce major changes in cell viability, confluence and morphology. Only slightly increased effects were observed by a few unique higher-order subsets of the CUSP9 protocol, which also contained disulfiram. This finding indicates that for the particular glioblastoma cell line used, the whole CUSP9 protocol could in principle be replaced solely with disulfiram. Notably, it may be worth testing in vitro the few slightly more potent higher-order subsets on primary patient derived glioblastoma cells. This work demonstrates the feasibility and potential of performing exhaustive in vitro evaluation of higher-order drug cocktails prior to subsequent assessment for clinical use. Although the experimental in vitro disease models are not optimal, they can still pinpoint which among all plausible subsets should be further considered. From a personalized therapy selection perspective, in vitro sensitivity testing of primary patient derived tumor cells could thereby advance from the current practice based on single drugs and only cytotoxicity readouts to also include higher-order drug cocktails and quantitative live-cell imaging.
9.	Cholujová, Dana, et al. (författare) Comparative study of four fluorescent probes for evaluation of natural killer cell cytotoxicity assays 2008 Ingår i: Immunobiology. - : Elsevier. - 0171-2985 .- 1878-3279. ; 213:8, s. 629-640 Tidskriftsartikel (refereegranskat)abstract Cytotoxicity is one of the major defence mechanisms against both virus-infected and tumor cells. Radioactive 51chromium (51Cr) release assay is a “gold standard” for assessment of natural killer (NK) cytolytic activity in vitro. Several disadvantages of this assay led us to design alternative tools based on flow cytometry analysis. Four different fluorescent dyes, calcein acetoxymethyl ester (CAM), carboxyfluorescein succinimidyl ester (CFSE), Vybrant DiO (DiO) and MitoTracker Green (MTG) were tested for labeling of NK target K-562 cells. Target staining stability, spontaneous release of fluorochromes and subsequent accumulation in bystander unstained cells were measured using fluorimetry and flow cytometry. Healthy donor peripheral blood mononuclear cells and affinity column purified NK cells were used as effectors coincubated with target K-562 cells at different E:T ratios for 3h and 90min, respectively. Fluorescent probe 7-amino-actinomycin D was used for live and dead cell discrimination. Bland–Altman statistical method was applied to measure true agreement for all CAM–51Cr, CFSE–51Cr, DiO–51Cr and MTG–51Cr pairs analyzed. Based on the data, none of the four proposed methods can be stated equivalent to the standard 51Cr release assay. Considering linear relationships between data obtained with four fluorochromes and 51Cr release assay as well as linear regression analysis with R2=0.9393 value for CAM–51Cr pair, we found the CAM assay to be the most closely related to the 51Cr assay.
10.	Christoffersson, Jonas, 1986-, et al. (författare) A Cardiac Cell Outgrowth Assay for Evaluating Drug Compounds Using a Cardiac Spheroid-on-a-Chip Device 2018 Ingår i: Bioengineering. - : MDPI AG. - 2306-5354. ; 5:2, s. 1-13 Tidskriftsartikel (refereegranskat)abstract Three-dimensional (3D) models with cells arranged in clusters or spheroids have emerged as valuable tools to improve physiological relevance in drug screening. One of the challenges with cells cultured in 3D, especially for high-throughput applications, is to quickly and non-invasively assess the cellular state in vitro. In this article, we show that the number of cells growing out from human induced pluripotent stem cell (hiPSC)-derived cardiac spheroids can be quantified to serve as an indicator of a drug’s effect on spheroids captured in a microfluidic device. Combining this spheroid-on-a-chip with confocal high content imaging reveals easily accessible, quantitative outgrowth data. We found that effects on outgrowing cell numbers correlate to the concentrations of relevant pharmacological compounds and could thus serve as a practical readout to monitor drug effects. Here, we demonstrate the potential of this semi-high-throughput “cardiac cell outgrowth assay” with six compounds at three concentrations applied to spheroids for 48 h. The image-based readout complements end-point assays or may be used as a non-invasive assay for quality control during long-term culture.
11.	Clausson, Carl-Magnus, 1985- (författare) Making Visible the Proximity Between Proteins 2014 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Genomic DNA is the template of life - the entity which is characterized by a self-sustaining anatomical development, regulated signaling processes, the ability to reproduce and to respond to stimuli. Through what is classically known as the central dogma, the genome is transcribed into mRNA, which in turn is translated into proteins. The proteins take part in most, if not all, cellular processes, and it is by unraveling these processes that we can begin to understand life and disease-causing mechanisms.In vitro and in vivo assays are two levels at which protein communication may be studied, and which permit manipulation and control over the proteins under investigation. But in order to retrieve a representation of the processes as close to reality as possible, in situ analysis may instead be applied as a complement to the other two levels of study. In situ PLA offers the ability to survey protein activity in tissue samples and primary cell lines, at a single cell level, detecting single targets in their natural unperturbed environment. In this thesis new developments of the in situ PLA are described, along with a new technique offering in situ enzyme-free detection of proximity between biomolecules.The dynamic range of in situ PLA has now been increased by several orders of magnitude to cover analogous ranges of protein expression; the output signals have been modified to offer a greater signal-to-noise ratio and to limit false-positive-rates while also extending the dynamic range further; simultaneous detection of multiple protein complexes is now possible; proximity-HCR is presented as a robust and inexpensive enzyme-free assay for protein complex detection.The thesis also covers descriptions on how the techniques may be simultaneously applied, also together with other techniques, for the multiple data-point acquisition required by the emerging realm of systems biology. A future perspective is presented for how much more information may be simultaneously acquired from tissue samples to describe biomolecular interactions in a new manner. This will allow new types of biomarkers and drugs to be discovered, and a new holistic understanding of life.
12.	Cros, Olivier (författare) Structural properties of the mastoid using image analysis and visualization 2017 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The mastoid, located in the temporal bone, houses an air cell system whose cells have a variation in size that can go far below current conventional clinical CT scanner resolution. Therefore, the mastoid air cell system is only partially represented in a CT scan. Where the conventional clinical CT scanner lacks level of minute details, micro-CT scanning provides an overwhelming amount of ne details. The temporal bone being one of the most complex in the human body, visualization of micro-CT scanning of this boneawakens the curiosity of the experimenter, especially with the correct visualization settings.This thesis first presents a statistical analysis determining the surface area to volume ratio of the mastoid air cell system of human temporal bone, from micro-CT scanning using methods previously applied for conventional clinical CT scans. The study compared current results with previous studies, with successive downsampling the data down to a resolution found in conventional clinical CT scanning. The results from the statistical analysis showed that all the small mastoid air cells, that cannot be detected in conventional clinical CT scans, do heavily contribute to the estimation of the surface area, and in consequence to the estimation of the surface area to volume ratio by a factor of about 2.6. Such a result further strengthens the idea of the mastoid to play an active role in pressure regulation and gas exchange.Discovery of micro-channels through specific use of a non-traditional transfer function was then reported, where a qualitative and a quantitative pre-analysis were performed and reported. To gain more knowledge about these micro-channels, a local structure tensor analysis was applied where structures are described in terms of planar, tubular, or isotropic structures. The results from this structural tensor analysis suggest these microchannels to potentially be part of a more complex framework, which hypothetically would provide a separate blood supply for the mucosa lining the mastoid air cell system.The knowledge gained from analysing the micro-channels as locally providing blood to the mucosa, led to the consideration of how inflammation of the mucosa could impact the pneumatization of the mastoid air cell system. Though very primitive, a 3D shape analysis of the mastoid air cell system was carried out. The mastoid air cell system was first represented in a compact form through a medial axis, from which medial balls could be used. The medial balls, representative of how large the mastoid air cells can be locally, were used in two complementary clustering methods, one based on the size diameter of the medial balls and one based on their location within the mastoid air cell system. From both quantitative and qualitative statistics, it was possible to map the clusters based on pre-defined regions already described in the literature, which opened the door for new hypotheses concerning the effect of mucosal inflammation on the mastoid pneumatization.Last but not least, discovery of other structures, previously unreported in the literature, were also visually observed and briefly discussed in this thesis. Further analysis of these unknown structures is needed.
13.	Desmarais, Samantha M, et al. (författare) High-throughput, Highly Sensitive Analyses of Bacterial Morphogenesis Using Ultra Performance Liquid Chromatography 2015 Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 290:52, s. 31090-31100 Tidskriftsartikel (refereegranskat)abstract The bacterial cell wall is a network of glycan strands crosslinked by short peptides (peptidoglycan); it is responsible for the mechanical integrity of the cell and shape determination. Liquid chromatography can be used to measure the abundance of the muropeptide subunits composing the cell wall. Characteristics such as the degree of cross-linking and average glycan strand length are known to vary across species. However, a systematic comparison among strains of a given species has yet to be undertaken, making it difficult to assess the origins of variability in peptidoglycan composition. We present a protocol for muropeptide analysis using ultra performance liquid chromatography (UPLC) and demonstrate that UPLC achieves resolution comparable with that of HPLC while requiring orders of magnitude less injection volume and a fraction of the elution time. We also developed a software platform to automate the identification and quantification of chromatographic peaks, which we demonstrate has improved accuracy relative to other software. This combined experimental and computational methodology revealed that peptidoglycan composition was approximately maintained across strains from three Gram-negative species despite taxonomical and morphological differences. Peptidoglycan composition and density were maintained after we systematically altered cell size in Escherichia coli using the antibiotic A22, indicating that cell shape is largely decoupled from the biochemistry of peptidoglycan synthesis. High-throughput, sensitive UPLC combined with our automated software for chromatographic analysis will accelerate the discovery of peptidoglycan composition and the molecular mechanisms of cell wall structure determination.
14.	Gemoll, T, et al. (författare) The impact of pre-analytical conditions on the serum proteome: heat-stabilization versus nitrogen storage 2013 Ingår i: Archives of physiology and biochemistry. - : Informa UK Limited. - 1744-4160 .- 1381-3455. ; 119:3, s. 100-107 Tidskriftsartikel (refereegranskat)
15.	Grannas, Karin, 1983- (författare) Improvements and Applications of in situ Proximity Ligation Assays 2015 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The cells building up the human body is in constant communication with each other. This communication is done through large complex networks of signaling pathways for inter- and intracellular signal transduction. The signaling activity regulates many important processes, for example cell death, proliferation and differentiation. Information within the signaling networks is communicated over the cell membrane, through the cytoplasm and entering the nucleus by protein activities such as protein-protein interactions (PPIs) and post translation modifications (PTMs). The cells adapts to their own environment, responding to multiple stimuli from their surroundings. This in combination with memory of previous responses, difference in cell cycles stages and sometimes altered genetic background generates heterogeneous cell populations in which every cell is slightly different from its neighbor. This calls for methods to study the activity of endogenous proteins in individual cells within a population.In situ proximity ligation assay (in situ PLA) was originally developed to visualize interaction between endogenous proteins in fixed cells and tissue and can also be applied to detect PTMs. This thesis describe the application of in situ PLA to study PPIs in signaling pathways and the work to further develop and improve techniques for proximity dependent detection. In paper I in situ PLA is used to study cross talk between the Hippo and the TGFβ signaling pathways. The study shows the complex formation by the transcription co-factors of the Hippo pathway, Yap and Taz, and the main effectors of the TGFβ pathway Smad2/3. Furthermore the density dependent localization of the interaction is described.Paper II presents a new version of the in situ PLA probes for simultaneous detection of multiple complexes. Visualization of various complexes involving EGFR, Her2 and Her3 is presented as a proof of concept.The efficiency of in situ PLA is limited by several factors, one being the design of PLA probes and oligonucleotide systems. Even upon proximal binding of the probes there is a risk of formation of non-circular ligation products, which cannot be amplified and detected. In Paper III two new PLA probes are presented aiming to reduce the formation of non-circular ligation product and hence increase the detection efficiency of in situ PLA.Paper IV presents a new method for detection of protein complexes and phosphorylation; proxHCR. ProxHCR combines signal amplification by enzyme free hybridization chain reaction (HCR) with the requirement of proximal binding of two affinity probes. As a proof of principle the method is used to detect multiple complexes and protein phosphorylation in fixed cells and tissue.
16.	Gustafsson, Johan, 1976, et al. (författare) Cellular limitation of enzymatic capacity explains glutamine addiction in cancers 2022 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Metabolism within the tumor microenvironment, where a complex mixture of different cell types resides in a nutrient-deprived surrounding, is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells’ preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common belief that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified a total of 233 potential metabolites that could support collaboration between cancer cells and cancer associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme constrained models for accurate prediction of metabolism in cells and tumor microenvironments.
17.	Hahn, Max, 1993- (författare) Characterizing the pancreatic "isletome" : 3D optical imaging to study diabetes 2022 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The pancreas is a specialised multipurpose organ, that can be separated into two major compartments: endocrine and exocrine. The exocrine part makes up the majority of the organ volume and functions to secrete digestive enzymes into the small intestine. Notably, endocrine islets of Langerhans are embedded and scattered in vast numbers throughout the exocrine space. These miniature functional units are composed of different cell types that secrete hormones into the blood stream. The most abundant islet-cell is the insulin-producing β-cell. Highly coordinated, the endocrine cells are the primary regulators of energy homeostasis in the body. Together, the collective islet volume constitutes the pancreatic “isletome”, a synchronised, complex and size-equilibrated system that is able to respond to various metabolic conditions. Indeed, environmental and/or genetic conditions often lead to impaired islet function and/or β-cell destruction leading to elevated blood glucose levels over time and eventually diabetes. Diabetes mellitus is a disease that currently affects more than 400 million individuals worldwide. As such, understanding pancreatic disease-related mechanisms is pivotal to the development of new and more effective therapeutic, or even curative, regimens. The deep location of the pancreas in the abdomen and the relatively low resolution of current clinical imaging approaches, however, render the pancreatic islets difficult to study when visually assessing endocrine function. Although non-invasive imaging techniques have yet to reach their full potential, post-mortem studies of the pancreas and rodent disease models offer unique insights into the process of diabetes disease dynamics.Diabetes induced by streptozotocin (STZ) is a widely used model system in pre-clinical research, where it is generally believed that the b-cells are depleted upon the administration of the drug. Yet, quantification of β-cell volume dynamics and underlying disease mechanisms have not been extensively described. Using optical projection tomography (OPT), light sheet fluorescence microscopy (LSFM) and advanced protocols for ex vivo whole organ three-dimensional (3D) imaging, this study demonstrated that STZ-induced β-cell depletion is modest, primarily affecting large islets, and is not the primary cause for the development of diabetes in STZ-diabetic mice. Combined with islet gene expression studies, the remaining β-cell volume in STZ-diabetic mice displayed a downregulation of glucose transporter type 2 (GLUT2), a transmembrane carrier vital for sensing blood glucose levels. Islet transplantation into the anterior chamber of the eye (ACE) reversed the STZ-induced hyperglycaemia and partially restored islet function, including GLUT2, but did not restore β-cell volume loss. Extensive 3D image datasets were generated as a resource to the research community. The combined results of this study indicated that STZ-induced hyperglycaemia is not caused by β-cell loss, but rather by dysfunctional β-cells and that recovery of islet function is restrained by continuous hyperglycaemia.3D imaging using OPT has proven to be a reliable technique in quantifying cellular/anatomical features of the mouse pancreas. However, the technique has rarely been applied to patient-derived tissues. Here, a label-free and non-destructive method was developed to assess clinical biopsies within hours of collection. Specifically, this study showed that autofluorescence-based imaging can be used to delineate tumours of the pancreas (pancreatic ductal adenocarcinoma, PDAC) in 3D, which may aid in identifying tumour margins in conjunction with resective surgery. Importantly, the protocol included a reversal pipeline so that other histological workflows could be applied to the same specimen. Furthermore, this study demonstrated that natural fluorescent substances in the endocrine cells provide sufficient contrast when quantifying both the volume and number of islets of Langerhans in the healthy pancreas. Altogether, the developed technique may provide a novel tool for the rapid 3D analysis of pancreatic biopsies that may complement and improve traditional pathological assessments.With the emergence of islet transplantation networks worldwide, access to fixed pancreatic tissues from diseased donors has dramatically improved. Hereby, the near instant autolysis of the pancreas post-mortem can generally be avoided, which provides the opportunity to quantitatively study the entire gland ex vivo within a conserved spatial context. Yet, mesoscopic 3D imaging of the pancreas (by OPT and/or LSFM) has been limited predominantly due to the obstacle of labelling larger tissue volumes. As such, a simple approach to antibody labelling and cellular imaging was developed in cubic centimetre-sized tissue cuboids that were mapped to the whole organ. By stitching the resultant datasets back into 3D space, this approach demonstrated how essentially any human organ may be analysed in full with high resolution. This technique was applied to pancreata from non-diabetic and type 2 diabetic (T2D) donors, analysing over 200 thousand islets, revealing features of the human pancreas that were not analysed in 3D previously, including high islet dense regions and intra-islet haemorrhaging. Crucially, this new technique may contribute to unveil a wealth of new insights into the complex pathophysiology of the “diabetic pancreas”.By applying the above method to the entire volume of the human pancreas, the absolute distribution and volume of insulin-positive cells in a pancreas from a donor with longstanding type 1 diabetes (T1D) was demonstrated for the first time. By dividing the 19 cm long organ into smaller pieces, followed by insulin labelling, OPT imaging and reconstruction in 3D space, approximately 173,000 insulin-positive objects were identified. By utilising tissue autofluorescence, the entire organ was reconstructed in 3D, together with blood vessels and ducts. These data indicated several important regional differences in β-cell mass, such as the uncinate process showing the highest density, which potentially reflects key aspects of disease dynamics. Furthermore, regions with a “punctated distribution” of single β-cells in close proximity to each other were identified. Although the significance of these observations needs to be elucidated, we speculate that these regions could be associated with pancreatic regeneration, which might permit the development of new interventions for clinical regenerative processes in the future. Altogether, this study represents the first whole organ account of β-cell distribution at the current level of resolution in an entire organ. As such, it may serve as an important advancement towards detailed whole organ analyses of endocrine cell identity/function, via a wide range of markers, in the study of normal anatomy and pathophysiology of the human pancreas.
18.	Katona, Borbala, et al. (författare) Antibody Validation Strategy for Nuclear Receptors. 2019 Ingår i: Methods in Molecular Biology. - New York, NY : Springer New York. - 1064-3745 .- 1940-6029. ; 1966, s. 79-99 Tidskriftsartikel (refereegranskat)abstract Antibodies are invaluable biological tools that we can use to detect the presence, location, or alteration of nuclear receptors. However, antibodies frequently cross-react with other proteins and their performance can vary from batch to batch, from application to application and from lab to lab. When each lot of antibody is not thoroughly validated for each assay, each sample type, and each lab and user, antibody-based assays can lead to flawed interpretations and reproducibility problems. In this chapter, we describe a scheme for thorough antibody validation, suitable for nuclear receptors. The method is based on using highly characterized positive and negative controls assembled into a validation tissue microarray (TMA). Through correlation of immunohistochemical staining (IHC) and mRNA levels over multiple tissues, use of current public databases, and assessment of binding to intended and nonintended targets using western blotting (WB), immunoprecipitation (IP), and mass spectrometry (MS), we describe a path for thoroughly validation of antibodies.
19.	Kortenkamp, Andreas, et al. (författare) Removing Critical Gaps in Chemical Test Methods by Developing New Assays for the Identification of Thyroid Hormone System-Disrupting Chemicals-The ATHENA Project 2020 Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 21:9 Tidskriftsartikel (refereegranskat)abstract The test methods that currently exist for the identification of thyroid hormone system-disrupting chemicals are woefully inadequate. There are currently no internationally validated in vitro assays, and test methods that can capture the consequences of diminished or enhanced thyroid hormone action on the developing brain are missing entirely. These gaps put the public at risk and risk assessors in a difficult position. Decisions about the status of chemicals as thyroid hormone system disruptors currently are based on inadequate toxicity data. The ATHENA project (Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies) has been conceived to address these gaps. The project will develop new test methods for the disruption of thyroid hormone transport across biological barriers such as the blood-brain and blood-placenta barriers. It will also devise methods for the disruption of the downstream effects on the brain. ATHENA will deliver a testing strategy based on those elements of the thyroid hormone system that, when disrupted, could have the greatest impact on diminished or enhanced thyroid hormone action and therefore should be targeted through effective testing. To further enhance the impact of the ATHENA test method developments, the project will develop concepts for better international collaboration and development in the area of thyroid hormone system disruptor identification and regulation.
20.	Langer, Krzysztof, et al. (författare) Rapid production and recovery of cell spheroids by automated droplet microfluidics 2019 Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Droplet microfluidics enables high throughput cell processing, analysis and screening by miniaturizing the reaction vessels to nano- or pico-liter water-in oil droplets, but like many other microfluidic formats, droplet microfluidics have not been interfaced with or automated by laboratory robotics. Here we demonstrate automation of droplet microfluidics based on an inexpensive liquid handling robot for the automated production of human scaffold-free cell spheroids, using pipette actuation and interfacing the pipetting tip with a droplet generating microfluidic chip. In this chip we produce highly mono-disperse 290μm droplets with diameter CV of 1.7%. By encapsulating cells in these droplets, we produce cell spheroids in droplets and recover them to standard formats at a throughput of 85000 spheroids per microfluidic circuit per hour. The viability of the cells in spheroids remains high after recovery only decreased by 4% starting from 96% after 16 hours incubation in nanoliter droplets. Scaffold-free cell spheroids and 3D tissue constructs recapitulate many aspects of functional human tissue more accurately than 2D or single cell cultures, but assembly methods for spheroids, e.g. hanging drop micro-plates, has had limited throughput. The increased throughput and decreased cost of our method enables spheroid production at the scale needed for lead discovery drug screening and approaches the cost where these micro tissues could be used as building blocks for organ scale regenerative medicine.
21.	Madsen, Rasmus Kirkegaard, 1979-, et al. (författare) Metabolic responses to change in disease activity during tumor necrosis factor inhibition in patients with rheumatoid arthritis 2012 Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 11:7, s. 3796-3804 Tidskriftsartikel (refereegranskat)abstract Assessment of disease activity in patients with rheumatoid arthritis (RA) is of importance in the evaluation of treatment. The most important measure of disease activity is the Disease Activity Score counted in 28 joints (DAS28). In this study, we evaluated whether metabolic profiling could complement current measures of disease activity. Fifty-six patients, in two separate studies, were followed for two years after commencing anti-TNF therapy. DAS28 was assessed, and metabolic profiles were recorded at defined time points. Correlations between metabolic profile and DAS28 scores were analyzed using multivariate statistics. The metabolic responses to lowering DAS28 scores varied in different patients but could predict DAS28 scores at the individual and subgroup level models. The erythrocyte sedimentation rate (ESR) component in DAS28 was most correlated to the metabolite data, pointing to inflammation as the primary effect driving metabolic profile changes. Patients with RA had differing metabolic response to changes in DAS28 following anti-TNF therapy. This suggests that discovery of new metabolic biomarkers for disease activity will derive from studies at the individual and subgroup level. Increased inflammation, measured as ESR, was the main common effect seen in metabolic profiles from periods associated with high DAS28.
22.	Mamontov, Eugen, 1955, et al. (författare) Mathematical models and numerical simulation results for oncogeny: Specific problems and different tools for various user communities 2008 Ingår i: Abstracts Booklet. CancerSim2008 — Euroconference on Modelling and Simulation of Cancer Growth and Therapy, 19-21 May, Turin, Italy; N. Bellomo and G. Forni (Chairmen) http://www.cancersim2008.org. Konferensbidrag (refereegranskat)
23.	McGinn, Steven, et al. (författare) New Technologies for DNA analysis-A review of the READNA Project. 2016 Ingår i: New Biotechnology. - : Elsevier BV. - 1876-4347 .- 1871-6784. Forskningsöversikt (refereegranskat)abstract The REvolutionary Approaches and Devices for Nucleic Acid analysis (READNA) project received funding from the European Commission for 4 1/2 years. The objectives of the project revolved around technological developments in nucleic acid analysis. The project partners have discovered, created and developed a huge body of insights into nucleic acid analysis, ranging from improvements and implementation of current technologies to the most promising sequencing technologies that constitute a 3(rd) and 4(th) generation of sequencing methods with nanopores and in situ sequencing, respectively.
24.	Rahman, Mashuqur, 1984-, et al. (författare) Enhanced detection of ATTR amyloid using a nanofibril-based assay 2021 Ingår i: Amyloid. - : Taylor and Francis Ltd.. - 1350-6129 .- 1744-2818. ; 28:3, s. 158-167 Tidskriftsartikel (refereegranskat)abstract More than 30 proteins and peptides have been found to form amyloid fibrils in human diseases. Fibrils formed by transthyretin (TTR) are associated with ATTR amyloidosis, affecting many vital organs, including the heart and peripheral nervous system. Congo red staining is the gold standard method for detection of amyloid deposits in tissue. However, Congo red staining and amyloid typing methods such as immunofluorescence labelling are limited to relatively large deposits. Detection of small ATTR deposits present at an early stage of the disease could enable timely treatment and prevent severe tissue damage. In this study, we developed an enhanced ATTR amyloid detection method that uses functionalised protein nanofibrils. Using this method, we achieved sensitive detection of monomeric TTR in a microplate immunoassay and immunofluorescence labelling of ex vivo tissue from two patients containing ATTR aggregates. The system's utility was confirmed on sections from a patient with AA amyloidosis and liver sections from inflamed mouse. These results suggest that the detection system constitutes important new technology for highly sensitive detection of microscopic amounts of ATTR amyloid deposited in tissue.
25.	Rinne, Sara S., et al. (författare) Targeting Tumor Cells Overexpressing the Human Epidermal Growth Factor Receptor 3 with Potent Drug Conjugates Based on Affibody Molecules 2022 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:6 Tidskriftsartikel (refereegranskat)abstract Increasing evidence suggests that therapy targeting the human epidermal growth factor receptor 3 (HER3) could be a viable route for targeted cancer therapy. Here, we studied a novel drug conjugate, ZHER3-ABD-mcDM1, consisting of a HER3-targeting affibody molecule, coupled to the cytotoxic tubulin polymerization inhibitor DM1, and an albumin-binding domain for in vivo half-life extension. ZHER3-ABD-mcDM1 showed a strong affinity to the extracellular domain of HER3 (K-D 6 nM), and an even stronger affinity (KD 0.2 nM) to the HER3-overexpressing pancreatic carcinoma cell line, BxPC-3. The drug conjugate showed a potent cytotoxic effect on BxPC-3 cells with an IC50 value of 7 nM. Evaluation of a radiolabeled version, [99mTc]Tc-ZHER3-ABD-mcDM1, showed a relatively high rate of internalization, with a 27% internalized fraction after 8 h. Further in vivo evaluation showed that it could target BxPC-3 (pancreatic carcinoma) and DU145 (prostate carcinoma) xenografts in mice, with an uptake peaking at 6.3 +/- 0.4% IA/g at 6 h post-injection for the BxPC-3 xenografts. The general biodistribution showed uptake in the liver, lung, salivary gland, stomach, and small intestine, organs known to express murine ErbB3 naturally. The results from the study show that ZHER3-ABD-mcDM1 is a highly potent and selective drug conjugate with the ability to specifically target HER3 overexpressing cells. Further pre-clinical and clinical development is discussed.
26.	Ronquist, Göran K, et al. (författare) Biochemical characterization of stallion prostasomes and comparison to their human counterparts 2013 Ingår i: Systems biology in reproductive medicine. - : Informa UK Limited. - 1939-6376 .- 1939-6368. ; 59:6, s. 297-303 Tidskriftsartikel (refereegranskat)abstract Release of nanometer-sized prostasomes into human and equine semen suggests essential functions in their relationships with sperm cells and the fertilization process. The two types of prostasomes displayed ultrastructural similarities, albeit the human prostasomes were somewhat larger than the stallion prostasomes. A high ratio of saturated fatty acids was characteristic for the two prostasome types. Electrophoretic separation systems revealed an equine prostasomal pattern different from that of human. The 21 distinctive low molecular weight protein spots in the 2D-gel (with no counterparts in human prostasomes) were identified via peptide mass fingerprinting, several of which may be different isoforms. Out of the three high molecular weight bands characteristic for human prostasomes (CD10, CD13, and CD26), CD10 and CD13 were retrieved in equine prostasomes. We present some new proteins of horse prostasomes not found in their human counterparts. Further studies are warranted to reveal the function of these proteins.
27.	Rugbjerg, Peter, 1988, et al. (författare) The future of self-selecting and stable fermentations 2020 Ingår i: Journal of Industrial Microbiology and Biotechnology. - : Oxford University Press (OUP). - 1367-5435 .- 1476-5535. ; 47:11, s. 993-1004 Forskningsöversikt (refereegranskat)abstract Unfavorable cell heterogeneity is a frequent risk during bioprocess scale-up and characterized by rising frequencies of low-producing cells. Low-producing cells emerge by both non-genetic and genetic variation and will enrich due to their higher specific growth rate during the extended number of cell divisions of large-scale bioproduction. Here, we discuss recent strategies for synthetic stabilization of fermentation populations and argue for their application to make cell factory designs that better suit industrial needs. Genotype-directed strategies leverage DNA-sequencing data to inform strain design. Self-selecting phenotype-directed strategies couple high production with cell proliferation, either by redirected metabolic pathways or synthetic product biosensing to enrich for high-performing cell variants. Evaluating production stability early in new cell factory projects will guide heterogeneity-reducing design choices. As good initial metrics, we propose production half-life from standardized serial-passage stability screens and production load, quantified as production-associated percent-wise growth rate reduction. Incorporating more stable genetic designs will greatly increase scalability of future cell factories through sustaining a high-production phenotype and enabling stable long-term production.
28.	Senkowski, Wojciech (författare) High-throughput screening using multicellular tumor spheroids to reveal and exploit tumor-specific vulnerabilities 2017 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract High-throughput drug screening (HTS) in live cells is often a vital part of the preclinical anticancer drug discovery process. So far, two-dimensional (2D) monolayer cell cultures have been the most prevalent model in HTS endeavors. However, 2D cell cultures often fail to recapitulate the complex microenvironments of in vivo tumors. Monolayer cultures are highly proliferative and generally do not contain quiescent cells, thought to be one of the main reasons for the anticancer therapy failure in clinic. Thus, there is a need for in vitro cellular models that would increase predictive value of preclinical research results. The utilization of more complex three-dimensional (3D) cell cultures, such as multicellular tumor spheroids (MCTS), which contain both proliferating and quiescent cells, has therefore been proposed. However, difficult handling and high costs still pose significant hurdles for application of MCTS for HTS.In this work, we aimed to develop novel assays to apply MCTS for HTS and drug evaluation. We also set out to identify cellular processes that could be targeted to selectively eradicate quiescent cancer cells. In Paper I, we developed a novel MCTS-based HTS assay and found that nutrient-deprived and hypoxic cancer cells are selectively vulnerable to treatment with inhibitors of mitochondrial oxidative phosphorylation (OXPHOS). We also identified nitazoxanide, an FDA-approved anthelmintic agent, to act as an OXPHOS inhibitor and to potentiate the effects of standard chemotherapy in vivo. Subsequently, in Paper II we applied the high-throughput gene-expression profiling method for MCTS-based drug screening. This led to discovery that quiescent cells up-regulate the mevalonate pathway upon OXPHOS inhibition and that the combination of OXPHOS inhibitors and mevalonate pathway inhibitors (statins) results in synergistic toxicity in this cell population. In Paper III, we developed a novel spheroid-based drug combination-screening platform and identified a set of molecules that synergize with nitazoxanide to eradicate quiescent cancer cells. Finally, in Paper IV, we applied our MCTS-based methods to evaluate the effects of phosphodiesterase (PDE) inhibitors in PDE3A-expressing cell lines.In summary, this work illustrates how MCTS-based HTS yields potential to reveal and exploit previously unrecognized tumor-specific vulnerabilities. It also underscores the importance of cell culture conditions in preclinical drug discovery endeavors.
29.	Sjöde, A., et al. (författare) Enzyme-based control of oxalic acid in the pulp and paper industry 2008 Ingår i: Enzyme and microbial technology. - : Elsevier BV. - 0141-0229 .- 1879-0909. ; 43:2, s. 78-83 Tidskriftsartikel (refereegranskat)abstract Enzymatically catalyzed decomposition of oxalic acid in bleaching filtrates from the pulp and paper industry offers a possibility to enduringly prevent oxalate scaling problems by specific removal of the oxalic acid in the system rather than by attempting to avoid calcium oxalate precipitation by countermeasures aiming at improved solubility. To achieve a broad evaluation of various oxalate-degrading enzymes and to cover conditions encountered in various types of processes, 16 different bleaching filtrates were collected from pulp mills engaged in mechanical pulping of softwood, mechanical pulping of aspen, and kraft pulping of softwood. A novel oxalate-degrading enzyme provided by Novozymes was compared with commercially available oxalate oxidase from barley and oxalate decarboxylase from Aspergillus niger. The activity of the enzymes in the filtrates was investigated using kinetic analysis and multivariate data analysis. Kinetic analysis indicated that the degradation rates were governed more by inhibitors in the filtrates than by the concentration of oxalic acid. Multivariate data analysis suggested links between high concentrations of certain compounds in the filtrates and high or low enzyme activity, as exemplified by the link between high concentrations of chelators in filtrates from mechanical pulping and low activity of oxalate oxidase from barley. All three enzymes could degrade oxalic acid in all filtrates, despite the fact that very high concentrations of residual hydrogen peroxide were found in several of the filtrates.
30.	Zenlander, Robin, et al. (författare) A wide scan of plasma proteins demonstrates thioredoxin reductase 1 as a potential new diagnostic biomarker for hepatocellular carcinoma 2023 Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 58:9, s. 998-1008 Tidskriftsartikel (refereegranskat)abstract Background: Patients with liver cirrhosis are recommended ultrasonography screening for early detection of hepatocellular carcinoma to increase the chances of curative treatment. However, ultrasonography alone lacks in sensitivity. Adding plasma biomarkers may increase the detection rate. We performed a broad exploratory analysis to find new plasma proteins with potential applicability for HCC screening in patients with cirrhosis. Methods: In a protein discovery cohort of 172 patients with cirrhosis or HCC, we screened for 481 proteins with suspension bead array or proximity extension assay. From these, 24 proteins were selected for further analysis in a protein verification cohort (n = 160), using ELISA, Luminex or an electrochemiluminescence platform. A cut-off model and a stepwise logistic regression model were used to find combinations of proteins with the best discriminatory performance between HCC and cirrhosis. Results: Stepwise logistic regression revealed alpha-fetoprotein (AFP), decarboxy-prothrombin (DCP), thioredoxin reductase 1 (TXNRD1), and fibroblast growth factor 21 (FGF21) as the proteins with the best discriminatory performance between HCC and cirrhosis. Adding TXNRD1 to DCP and AFP increased the AUC from 0.844 to 0.878, and combining AFP, DCP and TXNRD1 with age and sex resulted in an AUC of 0.920. FGF21, however, did not further increase the performance when including age and sex. Conclusion: In the present study, TXNRD1 improves the sensitivity and specificity of AFP and DCP as HCC screening tools in patients with cirrhosis. We suggest that TXNRD1 should be validated in prospective settings as a new complementary HCC biomarker together with AFP and DCP.
31.	Berg, Lotta (författare) Vad är döden för ett djur? - analys 2015 Ingår i: JP Djurnet. Annan publikation (populärvet., debatt m.m.)
32.	Elson, Frank, et al. (författare) TRIM Simulations Tool for μ + Stopping Fraction in Hydrostatic Pressure Cells 2023 Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 2462:1 Konferensbidrag (refereegranskat)abstract For quantum systems or materials, a common procedure for probing their behaviour is to tune electronic/magnetic properties using external parameters, e.g. temperature, magnetic field or pressure. Pressure application as an external stimuli is a widely used tool, where the sample in question is inserted into a pressure cell providing a hydrostatic pressure condition. Such device causes some practical problems when using in Muon Spin Rotation/Relaxation (μ +SR) experiments as a large proportion of the muons will be implanted in the pressure cell rather than in the sample, resulting in a higher background signal. This issue gets further amplified when the temperature dependent response from the sample is much smaller than that of the pressure cell,which may cause the sample response to be lost in the background and cause difficulties in aligning the sample within the beam. To tackle this issue, we have used pySRIM [1] to construct a practical and helpful simulation tool for calculating muon stopping fractions, specifically for the pressure cell setup at the μE1 beamline using the GPD spectrometer at the Paul Scherrer Institute, with the use of TRIM simulations. The program is used to estimate the number of muon stopping in both the sample and the pressure cell at a given momentum. The simultion tool is programmed into a GUI, making it accessible to user to approximate prior to their experiments at GPD what fractions will belong to the sample and the pressure cell in their fitting procedure.
33.	Klintberg, Anton, 1989, et al. (författare) Kalman filter for adaptive learning of two-dimensional look-up tables applied to OCV-curves for aged battery cells 2019 Ingår i: Control Engineering Practice. - : Elsevier BV. - 0967-0661. ; 84, s. 230-237 Tidskriftsartikel (refereegranskat)abstract In online automotive applications it is common to use look-up tables, or maps, to describe nonlinearities in component models that are to be valid over large operating ranges. If the component characteristics change with aging or wear, these look-up tables must be updated online. For 2-D look-up tables, the existing methods in the literature only adapt the observable parameters in the look-up table, which means that parameters in operation points that have not been visited for a long time may be far from their true values. In this work, correlations between different operating points are used to also update non-observable parameters of the look-up table. The method is applied to Open Circuit Voltage (OCV) curves for aged battery cells. From laboratory experimental data it is demonstrated that the proposed method can significantly reduce the average deviation from an aged OCV-curve compared to keeping the OCV-curve from the beginning of the cell's life, both for observable and non-observable parameters.
34.	Piraux, Guilain, 1990, et al. (författare) Multi-parameter sensor system for continuous and non-invasive online monitoring and control in bioreactors 2016 Ingår i: Biosensors 2016, 25-27 May 2016, Gothenburg Sweden. Konferensbidrag (övrigt vetenskapligt/konstnärligt)
35.	Rosén, Emil, et al. (författare) Inference of glioblastoma migration and proliferation rates using single time-point images 2023 Ingår i: Communications Biology. - : Springer Nature. - 2399-3642. ; 6:1 Tidskriftsartikel (refereegranskat)abstract Cancer cell migration is a driving mechanism of invasion in solid malignant tumors. Anti-migratory treatments provide an alternative approach for managing disease progression. However, we currently lack scalable screening methods for identifying novel anti-migratory drugs. To this end, we develop a method that can estimate cell motility from single end-point images in vitro by estimating differences in the spatial distribution of cells and inferring proliferation and diffusion parameters using agent-based modeling and approximate Bayesian computation. To test the power of our method, we use it to investigate drug responses in a collection of 41 patient-derived glioblastoma cell cultures, identifying migration-associated pathways and drugs with potent anti-migratory effects. We validate our method and result in both in silico and in vitro using time-lapse imaging. Our proposed method applies to standard drug screen experiments, with no change needed, and emerges as a scalable approach to screen for anti-migratory drugs. The spatial positioning of cultured glioblastoma cells is used to estimate cell motility and drug effects from single end-point images in vitro.
36.	Trossbach, Martin, et al. (författare) A Portable, Negative-Pressure Actuated, Dynamically Tunable Microfluidic Droplet Generator 2022 Ingår i: Micromachines. - : MDPI AG. - 2072-666X. ; 13:11, s. 1823-1823 Tidskriftsartikel (refereegranskat)abstract Droplet microfluidics utilize a monodisperse water-in-oil emulsion, with an expanding toolbox offering a wide variety of operations on a range of droplet sizes at high throughput. However, translation of these capabilities into applications for non-expert laboratories to fully harness the inherent potential of microscale manipulations is woefully trailing behind. One major obstacle is that droplet microfluidic setups often rely on custom fabricated devices, costly liquid actuators, and are not easily set up and operated by non-specialists. This impedes wider adoption of droplet technologies in, e.g., the life sciences. Here, we demonstrate an easy-to-use minimal droplet production setup with a small footprint, built exclusively from inexpensive commercially sourced parts, powered and controlled by a laptop. We characterize the components of the system and demonstrate production of droplets ranging in volume from 3 to 21 nL in a single microfluidic device. Furthermore, we describe the dynamic tuning of droplet composition. Finally, we demonstrate the production of droplet-templated cell spheroids from primary cells, where the mobility and simplicity of the setup enables its use within a biosafety cabinet. Taken together, we believe this minimal droplet setup is ideal to drive broad adoption of droplet microfluidics technology.
37.	Zhdanov, Vladimir, 1952 (författare) Spatio-temporal aspects of the interplay of cancer and the immune system 2019 Ingår i: Journal of Biological Physics. - : Springer Science and Business Media LLC. - 0092-0606 .- 1573-0689. ; 45:4, s. 395-400 Tidskriftsartikel (refereegranskat)abstract The conventional mean-field kinetic models describing the interplay of cancer and the immune system are temporal and predict exponential growth or elimination of the population of tumour cells provided their number is small and their effect on the immune system is negligible. More complex kinetics are associated with non-linear features of the response of the immune system. The generic model presented in this communication takes into account that the rates of the birth and death of tumour cells inside a tumour spheroid can significantly depend on the radial coordinate due to diffusion limitations in the supply of nutrients and/or transport of the species (cells and proteins) belonging to the immune system. In this case, non-trivial kinetic regimes are shown to be possible even without appreciable perturbation of the immune system.
38.	Lind-Halldén, Christina, et al. (författare) Genetic variation in the syntaxin-binding protein STXBP5 in type 1 von Willebrand disease patients 2018 Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag. - 2567-689X .- 0340-6245. ; 118:8, s. 1382-1389 Tidskriftsartikel (refereegranskat)abstract von Willebrand factor (VWF) levels in healthy individuals and in patients with type 1 von Willebrand disease (VWD) are influenced by genetic variation in several genes, for example, VWF, ABO and STXBP5. Here, we comprehensively screen for STXBP5 variants and investigate their association with type 1 VWD in Swedish patients and controls. The coding region of the STXBP5 gene was re-sequenced in 107 type 1 VWD patients and the detected variants were genotyped in the type 1 VWD population and a Swedish control population (464 individuals). The functional effects of missense alleles were predicted in silico and the pattern of genetic variation in STXBP5 was analysed. Re-sequencing of 107 type 1 VWD patients identified three missense and three synonymous variants in the coding sequence of STXBP5. The low-frequency missense variants rs144099092 (0.005) and rs148830578 (0.029) were predicted to be damaging, but were not accumulated in patients. No other rare candidate mutations were detected. STXBP5 showed a high level of linkage disequilibrium and a low overall nucleotide diversity of π = 3.2 × 10-4 indicating intolerance to variants affecting protein function. Three previously type 1 VWD-associated single nucleotide polymorphisms were located on one haplotype that showed an increased frequency in patients versus controls. No differences in messenger ribonucleic acid abundance among haplotypes could be found using Genotype-Tissue Expression project data. In conclusion, a haplotype containing the STXBP5 Asn436Ser (rs1039084) mutation is associated with type 1 VWD and no rare STXBP5 mutations contribute to type 1 VWD in the Swedish population.
39.	Palsdottir, Vilborg, 1979, et al. (författare) Maternal Saturated-Fat Diet During Lactation Improves Glucose Tolerance and Influences Gene Expression in Adult Mice 2009 Ingår i: Journal of Nutrigenetics and Nutrigenomics. - 1661-6499 .- 1661-6758. ; 2:4-5, s. 216-216 Konferensbidrag (refereegranskat)
40.	Palsdottir, Vilborg, 1979, et al. (författare) Prenatal essential fatty acid deficiency in mice results in long-term gender-specific effects on body weight and glucose metabolism 2011 Ingår i: Molecular Medicine Reports. - : Spandidos Publications. - 1791-2997 .- 1791-3004. ; 4:4, s. 731-737 Tidskriftsartikel (refereegranskat)abstract Essential fatty acids are important for normal growth and development in early life. However, the long-term effects of prenatal essential fatty acid deficiency (EFAD) on the adult metabolism remain to be determined. The aim of this study was to investigate the effects of an EFAD diet given to mice during late gestation on body weight and body composition, and metabolism in the adult offspring. Pregnant dams were given an EFAD or a control diet during the last 10 days of gestation. After delivery, all mice were fed normal chow and the body weight of the offspring was measured weekly. Furthermore, food intake, energy expenditure and intraperitoneal glucose tolera-nce were analysed in the adult offspring in addition to body composition (analysed by dual-energy X-ray absorptiometry), plasma levels of leptin, triglycerides and cholesterol. The body weight was lower in the EFAD offspring as compared to the controls during the first 4 weeks of age, and remained lower in the females throughout the study. Lean body mass and plasma leptin levels were also lower in the female EFAD offspring as compared to the controls. Male EFAD offspring were found to have higher fasting glucose and insulin levels as well as higher insulin levels during the glucose tolerance test compared to the controls. However, no differences were found in blood lipids, food intake or energy expenditure between EFAD and control mice of either gender. These results demonstrate that an EFAD diet given during the last 10 days of gestation results in long-term gender-specific effects on body weight and insulin sensitivity in the adult offspring.
41.	Andersson, Annika, et al. (författare) Development of parallel reaction monitoring assays for cerebrospinal fluid proteins associated with Alzheimer's disease 2019 Ingår i: Clinica Chimica Acta. - : Elsevier B.V.. - 0009-8981 .- 1873-3492. ; 494, s. 79-93 Tidskriftsartikel (refereegranskat)abstract Detailed knowledge of protein changes in cerebrospinal fluid (CSF) across healthy and diseased individuals would provide a better understanding of the onset and progression of neurodegenerative disorders. In this study, we selected 20 brain-enriched proteins previously identified in CSF by antibody suspension bead arrays (SBA) to be potentially biomarkers for Alzheimer's disease (AD) and verified these using an orthogonal approach. We examined the same set of 94 CSF samples from patients affected by AD (including preclinical and prodromal), mild cognitive impairment (MCI), non-AD dementia and healthy individuals, which had previously been analyzed by SBA. Twenty-eight parallel reaction monitoring (PRM) assays were developed and 13 of them could be validated for protein quantification. Antibody profiles were verified by PRM. For seven proteins, the antibody profiles were highly correlated with the PRM results (r > 0.7) and GAP43, VCAM1 and PSAP were identified as potential markers of preclinical AD. In conclusion, we demonstrate the usefulness of targeted mass spectrometry as a tool for the orthogonal verification of antibody profiling data, suggesting that these complementary methods can be successfully applied for comprehensive exploration of CSF protein levels in neurodegenerative disorders.
42.	Cann, Sophie Le, et al. (författare) Spatio-temporal evolution of hydroxyapatite crystal thickness at the bone-implant interface 2020 Ingår i: Acta Biomaterialia. - : Elsevier BV. - 1878-7568 .- 1742-7061. ; 116, s. 391-399 Tidskriftsartikel (refereegranskat)abstract A better understanding of bone nanostructure around the bone-implant interface is essential to improve longevity of clinical implants and decrease failure risks. This study investigates the spatio-temporal evolution of mineral crystal thickness and plate orientation in newly formed bone around the surface of a metallic implant. Standardized coin-shaped titanium implants designed with a bone chamber were inserted into rabbit tibiae for 7 and 13 weeks. Scanning measurements with micro-focused small-angle X-ray scattering (SAXS) were carried out on newly formed bone close to the implant and in control mature cortical bone. Mineral crystals were thinner close to the implant (1.8 ± 0.45 nm at 7 weeks and 2.4 ± 0.57 nm at 13 weeks) than in the control mature bone tissue (2.5 ± 0.21 nm at 7 weeks and 2.8 ± 0.35 nm at 13 weeks), with increasing thickness over healing time (+30 % in 6 weeks). These results are explained by younger bone close to the implant, which matures during osseointegration. Thinner mineral crystals parallel to the implant surface within the first 100 µm close to the implant indicate that the implant affects bone ultrastructure close to the implant, potentially due to heterogeneous interfacial stresses, and suggest a longer maturation process of bone tissue and difficulty in binding to the metal. The bone growth kinetics within the bone chamber was derived from the spatio-temporal evolution of bone tissue's nanostructure, coupled with microtomographic imaging. The findings indicate that understanding mineral crystal thickness or plate orientation can improve our knowledge of osseointegration.
43.	Cartwright, Ashley, et al. (författare) Characterization of large in-frame von Willebrand factor deletions highlights differing pathogenic mechanisms 2020 Ingår i: Blood Advances. - 2473-9529 .- 2473-9537. ; 4:13, s. 2979-2990 Tidskriftsartikel (refereegranskat)abstract Copy number variation (CNV) is known to cause all von Willebrand disease (VWD) types, although the associated pathogenic mechanisms involved have not been extensively studied. Notably, in-frame CNV provides a unique opportunity to investigate how specific von Willebrand factor (VWF) domains influence the processing and packaging of the protein. Using multiplex ligation-dependent probe amplification, this study determined the extent to which CNV contributed to VWD in the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease cohort, highlighting in-frame deletions of exons 3, 4-5, 32-34, and 33-34. Heterozygous in vitro recombinant VWF expression demonstrated that, although deletion of exons 3, 32-34, and 33-34 all resulted in significant reductions in total VWF (P < .0001, P < .001, and P < .01, respectively), only deletion of exons 3 and 32-34 had a significant impact on VWF secretion (P < .0001). High-resolution microscopy of heterozygous and homozygous deletions confirmed these observations, indicating that deletion of exons 3 and 32-34 severely impaired pseudo-Weibel-Palade body (WPB) formation, whereas deletion of exons 33-34 did not, with this variant still exhibiting pseudo-WPB formation similar to wild-type VWF. In-frame deletions in VWD, therefore, contribute to pathogenesis via moderate or severe defects in VWF biosynthesis and secretion.
44.	Delfani, Payam (författare) Biomarker Discovery in Autoimmune Diseases using Antibody Microarrays : Targeting Systemic Lupus Erythematosus 2016. - 200 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)
45.	Dodig-Crnkovic, Tea, et al. (författare) Facets of individual-specific health signatures determined from longitudinal plasma proteome profiling 2020 Ingår i: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 57 Tidskriftsartikel (refereegranskat)abstract Background: Precision medicine approaches aim to tackle diseases on an individual level through molecular profiling. Despite the growing knowledge about diseases and the reported diversity of molecular phenotypes, the descriptions of human health on an individual level have been far less elaborate. Methods: To provide insights into the longitudinal protein signatures of well-being, we profiled blood plasma collected over one year from 101 clinically healthy individuals using multiplexed antibody assays. After applying an antibody validation scheme, we utilized > 700 protein profiles for in-depth analyses of the individuals' short-term health trajectories. Findings: We found signatures of circulating proteomes to be highly individual-specific. Considering technical and longitudinal variability, we observed that 49% of the protein profiles were stable over one year. We also identified eight networks of proteins in which 11-242 proteins covaried over time. For each participant, there were unique protein profiles of which some could be explained by associations to genetic variants. Interpretation: This observational and non-interventional study identifyed noticeable diversity among clinically healthy subjects, and facets of individual-specific signatures emerged by monitoring the variability of the circulating proteomes over time. To enable more personal hence precise assessments of health states, longitudinal profiling of circulating proteomes can provide a valuable component for precision medicine approaches.
46.	Fletcher, Eugene, 1986, et al. (författare) Editorial: Genomic strategies for efficient microbial cell factories 2022 Ingår i: Frontiers in Bioengineering and Biotechnology. - : Frontiers Media SA. - 2296-4185. ; 10 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
47.	Gharehbaghi, Arash, et al. (författare) A pattern recognition framework for detecting dynamic changes on cyclic time series 2015 Ingår i: Pattern Recognition. - : Elsevier. - 0031-3203 .- 1873-5142. ; 48:3, s. 696-708 Tidskriftsartikel (refereegranskat)abstract This paper proposes a framework for binary classification of the time series with cyclic characteristics. The framework presents an iterative algorithm for learning the cyclic characteristics by introducing the discriminative frequency bands (DFBs) using the discriminant analysis along with k-means clustering method. The DFBs are employed by a hybrid model for learning dynamic characteristics of the time series within the cycles, using statistical and structural machine learning techniques. The framework offers a systematic procedure for finding the optimal design parameters associated with the hybrid model. The proposed model is optimized to detect the changes of the heart sound recordings (HSRs) related to aortic stenosis. Experimental results show that the proposed framework provides efficient tools for classification of the HSRs based on the heart murmurs. It is also evidenced that the hybrid model, proposed by the framework, substantially improves the classification performance when it comes to detection of the heart disease.
48.	Gharehbaghi, Arash, et al. (författare) An Automatic Tool for Pediatric Heart Sounds Segmentation Annan publikation (övrigt vetenskapligt/konstnärligt)abstract In this paper, we present a novel algorithm for pediatric heart sound segmentation, incorporated into a graphical user interface. The algorithm employs both the Electrocardiogram (ECG) and Phonocardiogram (PCG) signals for an efficient segmentation under pathological circumstances.First, the ECG signal is invoked in order to determine the beginning and end points of each cardiac cycle by using wavelet transform technique. Then, first and second heart sounds within the cycles are identified over the PCG signal by paying attention to the spectral properties of the sounds. The algorithm is applied on 120 recordings of normal and pathological children, totally containing 1976 cardiac cycles. The accuracy of the segmentation algorithm is 97% for S1 and 94% for S2 identification while all the cardiac cycles are correctly determined.
49.	Gharehbaghi, Arash, et al. (författare) Severity assessments of aortic stenosis using intelligent phonocardiography Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Objectives: To study capabilities of the intelligent phonocardiography (IPCG) in automatic grading severity of the aortic stenosis (AS).Methods: Phonocardiogram signals were recorded from the patients with AS, as diagnosed by echocardiography. The patient group is comprised of signals, recorded from 5 patients (2 recordings from each), mostly elderly referrals (>60 years) with mild to severe AS. An advanced processing algorithm, consisted of the wavelet transform and the stepwise regression analysis, characterizes the systolic murmur caused by the AS in order to predict the 5 indicators; mean pressure gradient over the aortic valve (MPG), maximum jet velocity (MJV), aortic valve area (AVA), velocity time integral and the ejection period. The automatic assessment is performed by an artificial neural network using the predicted values of the indicators as the input data. Reliability of the IPCG is validated by applying repeated random sub-sampling (RRSS) with 70%/30% of the training/testing data, and calculating the accuracy. The RRSS is also employed to validate reproducibility of the IPCG by using 70% of the signals for training and the second recording of the same individuals for testing.Results: Accuracy of the IPCG is estimated to be and (95% confidence interval) for the reliability and the reproducibility, respectively. Linear correlation between the characterized systolic murmur and the MPG (r>0.81), the MJV (r>0.82) and the AVA (r>0.85) is observed.Conclusions: The IPCG has the potential to objectively serve as a clinical tool for grading severity of the aortic stenosis.
50.	Hafid, Abdelakram, et al. (författare) Full Impedance Cardiography Measurement Device Using Raspberry PI3 and System-on-Chip Biomedical Instrumentation Solutions 2018 Ingår i: IEEE journal of biomedical and health informatics. - : IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC. - 2168-2194 .- 2168-2208. ; 22:6, s. 1883-1894 Tidskriftsartikel (refereegranskat)abstract Impedance cardiography (ICG) is a noninvasive method for monitoring cardiac dynamics using electrical bioimpedance (EBI) measurements. Since its appearance more than 40 years ago, ICG has been used for assessing hemodynamic parameters. This paper presents a measurement system based on two System on Chip (SoC) solutions and Raspberry PI, implementing both a full three-lead ECG recorder and an impedance cardiographer, for educational and research development purposes. Raspberry PI is a platform supporting Do-I t-Yourself project and education applications across the world. The development is part of Biosignal PI, an open hardware platform focusing in quick prototyping of physiological measurement instrumentation. The SoC used for sensing cardiac biopotential is the ADAS1000, and for the EBI measurement is the AD5933. The recordings were wirelessly transmitted through Bluetooth to a PC, where the waveforms were displayed, and hemodynamic parameters such as heart rate, stroke volume, ejection time and cardiac output were extracted from the ICG and ECG recordings. These results show how Raspberry PI can be used for quick prototyping using relatively widely available and affordable components, for supporting developers in research and engineering education. The design and development documents will be available on www.BiosignalPl.com, for open access under a Non Commercial-Share A like 4.0 International License.

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