| 1. |
- Gustafsson, Erika, et al.
(författare)
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Directed evolution of chemotaxis inhibitory protein of Staphylococcus aureus generates biologically functional variants with reduced interaction with human antibodies
- 2010
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Ingår i: Protein Engineering Design & Selection. - : Oxford University Press (OUP). - 1741-0126 .- 1741-0134. ; 23:2, s. 91-101
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Tidskriftsartikel (refereegranskat)abstract
- Chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) is a protein that binds and blocks the C5a receptor (C5aR) and formylated peptide receptor, thereby inhibiting the immune cell recruitment associated with inflammation. If CHIPS was less reactive with existing human antibodies, it would be a promising anti-inflammatory drug candidate. Therefore, we applied directed evolution and computational/rational design to the CHIPS gene in order to generate new CHIPS variants displaying lower interaction with human IgG, yet retaining biological function. The optimization was performed in four rounds: one round of random mutagenesis to add diversity into the CHIPS gene and three rounds of DNA recombination by Fragment INduced Diversity (FIND((R))). Every round was screened by phage selection and/or ELISA for decreased interaction with human IgG and retained C5aR binding. The mean binding of human anti-CHIPS IgG decreased with every round of evolution. For further optimization, new amino acid substitutions were introduced by rational design, based on the mutations identified during directed evolution. Finally, seven CHIPS variants with low interaction with human IgG and retained C5aR blocking capacity could be identified.
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| 2. |
- Bivik Stadler, Caroline, 1986-, et al.
(författare)
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Proactive Construction of an Annotated Imaging Database for Artificial Intelligence Training
- 2021
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Ingår i: Journal of digital imaging. - : Springer-Verlag New York. - 0897-1889 .- 1618-727X. ; 34, s. 105-115
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Tidskriftsartikel (refereegranskat)abstract
- Artificial intelligence (AI) holds much promise for enabling highly desired imaging diagnostics improvements. One of the most limiting bottlenecks for the development of useful clinical-grade AI models is the lack of training data. One aspect is the large amount of cases needed and another is the necessity of high-quality ground truth annotation. The aim of the project was to establish and describe the construction of a database with substantial amounts of detail-annotated oncology imaging data from pathology and radiology. A specific objective was to be proactive, that is, to support undefined subsequent AI training across a wide range of tasks, such as detection, quantification, segmentation, and classification, which puts particular focus on the quality and generality of the annotations. The main outcome of this project was the database as such, with a collection of labeled image data from breast, ovary, skin, colon, skeleton, and liver. In addition, this effort also served as an exploration of best practices for further scalability of high-quality image collections, and a main contribution of the study was generic lessons learned regarding how to successfully organize efforts to construct medical imaging databases for AI training, summarized as eight guiding principles covering team, process, and execution aspects.
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| 3. |
- Demmelmaier, Ingrid, 1960-, et al.
(författare)
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Does exercise intensity matter for fatigue during (neo-)adjuvant cancer treatment? The Phys-Can randomized clinical trial
- 2021
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : Wiley. - 0905-7188 .- 1600-0838. ; 31:5, s. 1144-1159
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Tidskriftsartikel (refereegranskat)abstract
- Exercise during cancer treatment improves cancer-related fatigue (CRF), but the importance of exercise intensity for CRF is unclear. We compared the effects of high- vs low-to-moderate-intensity exercise with or without additional behavior change support (BCS) on CRF in patients undergoing (neo-)adjuvant cancer treatment. This was a multicenter, 2x2 factorial design randomized controlled trial (Clinical Trials NCT02473003) in Sweden. Participants recently diagnosed with breast (n = 457), prostate (n = 97) or colorectal (n = 23) cancer undergoing (neo-)adjuvant treatment were randomized to high intensity (n = 144), low-to-moderate intensity (n = 144), high intensity with BCS (n = 144) or low-to-moderate intensity with BCS (n = 145). The 6-month exercise intervention included supervised resistance training and home-based endurance training. CRF was assessed by Multidimensional Fatigue Inventory (MFI, five subscales score range 4-20), and Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F, score range 0-52). Multiple linear regression for main factorial effects was performed according to intention-to-treat, with post-intervention CRF as primary endpoint. Overall, 577 participants (mean age 58.7 years) were randomized. Participants randomized to high- vs low-to-moderate-intensity exercise had lower physical fatigue (MFI Physical Fatigue subscale; mean difference −1.05 [95% CI: −1.85, −0.25]), but the difference was not clinically important (ie <2). We found no differences in other CRF dimensions and no effect of additional BCS. There were few minor adverse events. For CRF, patients undergoing (neo-)adjuvant treatment for breast, prostate or colorectal cancer can safely exercise at high- or low-to-moderate intensity, according to their own preferences. Additional BCS does not provide extra benefit for CRF in supervised, well-controlled exercise interventions.
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| 4. |
- Alvez, Maria Bueno, et al.
(författare)
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Next generation pan-cancer blood proteome profiling using proximity extension assay
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- A comprehensive characterization of blood proteome profiles in cancer patients can contribute to a better understanding of the disease etiology, resulting in earlier diagnosis, risk stratification and better monitoring of the different cancer subtypes. Here, we describe the use of next generation protein profiling to explore the proteome signature in blood across patients representing many of the major cancer types. Plasma profiles of 1463 proteins from more than 1400 cancer patients are measured in minute amounts of blood collected at the time of diagnosis and before treatment. An open access Disease Blood Atlas resource allows the exploration of the individual protein profiles in blood collected from the individual cancer patients. We also present studies in which classification models based on machine learning have been used for the identification of a set of proteins associated with each of the analyzed cancers. The implication for cancer precision medicine of next generation plasma profiling is discussed.
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| 5. |
- Andersson, Emma K, 1978-, et al.
(författare)
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Small molecule screening using a whole cell viral replication reporter gene assay identifies 2-{[2-(benzoylamino)benzoyl]amino}-benzoic acid as a novel anti-adenoviral compound
- 2010
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American society for microbiology. - 0066-4804 .- 1098-6596. ; 54:9, s. 3871-3877
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Tidskriftsartikel (refereegranskat)abstract
- Adenovirus infections are widespread in society and are occasionally associated with severe, but rarely with life-threatening, disease in otherwise healthy individuals. In contrast, adenovirus infections present a real threat to immunocompromised individuals and can result in disseminated and fatal disease. The number of patients undergoing immunosuppressive therapy for solid organ or hematopoietic stem cell transplantation is steadily increasing, as is the number of AIDS patients, and this makes the problem of adenovirus infections even more urgent to solve. There is no formally approved treatment of adenovirus infections today, and existing antiviral agents evaluated for their anti-adenoviral effect give inconsistent results. We have developed a whole cell-based assay for high-throughput screening of potential anti-adenoviral compounds. The assay is unique in that it is based on a replication competent adenovirus type 11p GFP-expressing vector (RCAd11pGFP). This allows measurement of fluorescence changes as a direct result of RCAd11pGFP genome expression. Using this assay, we have screened 9,800 commercially available small organic compounds. Initially, we observed approximately 400 compounds that inhibited adenovirus expression in vitro by >/= 80% but only 24 were later confirmed as dose-dependent inhibitors of adenovirus. One compound in particular, 2-[[2-(benzoylamino)benzoyl]amino]-benzoic acid, turned out to be a potent inhibitor of adenovirus replication.
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| 6. |
- Bratulic, Sinisa, 1981, et al.
(författare)
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Noninvasive detection of any-stage cancer using free glycosaminoglycans.
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:50
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Tidskriftsartikel (refereegranskat)abstract
- Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported ~10% sensitivity to detect stage I cancer in a screening population and specific types, such as brain or genitourinary tumors, remain undetectable. We investigated urine and plasma free glycosaminoglycan profiles (GAGomes) as tumor metabolism biomarkers for multi-cancer early detection (MCED) of 14 cancer types using 2,064 samples from 1,260 cancer or healthy subjects. We observed widespread cancer-specific changes in biofluidic GAGomes recapitulated in an in vivo cancer progression model. We developed three machine learning models based on urine (Nurine = 220 cancer vs. 360 healthy) and plasma (Nplasma = 517 vs. 425) GAGomes that can detect any cancer with an area under the receiver operating characteristic curve of 0.83-0.93 with up to 62% sensitivity to stage I disease at 95% specificity. Undetected patients had a 39 to 50% lower risk of death. GAGomes predicted the putative cancer location with 89% accuracy. In a validation study on a screening-like population requiring ≥ 99% specificity, combined GAGomes predicted any cancer type with poor prognosis within 18 months with 43% sensitivity (21% in stage I; N = 121 and 49 cases). Overall, GAGomes appeared to be powerful MCED metabolic biomarkers, potentially doubling the number of stage I cancers detectable using genomic biomarkers.
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| 7. |
- Cárdenas, Marité, et al.
(författare)
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DNA compaction by cationic surfactant in solution and at polystyrene particle solution interfaces: a dynamic light scattering study
- 2004
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Ingår i: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9084. ; 6:7, s. 1603-1607
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Tidskriftsartikel (refereegranskat)abstract
- The effect of cationic surfactant on the compaction of DNA both in bulk solution and on polystyrene particles has been studied by dynamic light scattering. DNA undergoes a transition from a semiflexible coil to a more compact globule in aqueous solution as a consequence of cationic surfactant binding. Thus the hydrodynamic radius of DNA decreases from 107 nm to about 50 nm in the presence of cationic surfactant. Such compaction is also observed on DNA coated polystyrene particles. In this case, the hydrodynamic layer thickness of DNA coated particles is reduced from 36 to 5 nm in the presence of cetyltrimethylammonium bromide.
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| 8. |
- Cárdenas, Marité, et al.
(författare)
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Interaction between DNA and charged colloids could be hydrophobically driven
- 2005
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Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1526-4602 .- 1525-7797. ; 6:2, s. 832-837
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Tidskriftsartikel (refereegranskat)abstract
- The interaction of DNA with amino-functionalized polystyrene particles has been studied by using a dynamic light scattering (DLS) technique. In 10 mM NaBr solution the particles have a hydrodynamic radius of 76 nm and the DNA macromolecule investigated (double stranded) has a hydrodynamic radius of 107 nm. At very low DNA concentrations, DNA adopts a flat conformation on the particle surface. If the DNA concentration is increased above 0.1 mu g/mL, the thickness of the DNA layer increases, suggesting the presence of large loops and tails. Although the particles contain primary amino groups, they have a negative net charge under the conditions used in this work. Thus, the driving force for DNA adsorption is not of electrostatic origin but rather due to a hydrophobic effect. Addition of cationic surfactant to the DNA-precoated amino functionalized particles induces changes in the adsorbed layer conformation, in agreement with the coadsorption of cationic surfactant.
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| 9. |
- Costa, Telma, et al.
(författare)
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Association of a hydrophobically modified polyelectrolyte and a block copolymer followed by fluorescence techniques
- 2009
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Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 113:18, s. 6194-6204
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Tidskriftsartikel (refereegranskat)abstract
- By using absorption and fluorescence (steady-state and time-resolved) techniques the interaction between a poly(acrylic acid) PAA, randomly grafted with pyrene (Py) units (PAAMePy55) and a triblock copolymer of poly(ethylene oxide) and poly(propylene oxide) (EO20PO68EO20, P123) was investigated. From the fluorescence data it is shown that upon addition of P123 a decrease of the (pyrene-pyrene, Py-Py) intramolecular association, i.e., a decrease of dynamic and static excimer formation, is observed. Timeresolved fluorescence data reveal the existence of two types of monomers (monomers that are able to form excimer, MAGRE, and isolated monomers) and two excimers. Addition of P123 causes also an increase of the amount of isolated Py monomers. The overall fluorescence data suggest that the PAAMePy55 and the P123 block copolymer associate strongly at low pH, leading to the formation of P123 micelles surrounded by one PAAMePy55 chain, where the pyrene groups are located at the PPO/PEO interface of the P123 micelles. Steady-state fluorescence results also showed that an excess of P123 micelles in solution is required for the association to occur. At high pH (pH 9 and above), the situation is less clear, the steady-state (particularly in the I1/I3 ratio) and time-resolved fluorescence results indicate a contact between the pyrene groups and PEO, which then would imply that there may be an interaction, but much weaker than at low pH.
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| 10. |
- Costa, Telma, et al.
(författare)
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Complex Formation between a Fluorescently-Labeled Polyelectrolyte and a Triblock Copolymer
- 2009
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Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 113:18, s. 6205-6214
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Tidskriftsartikel (refereegranskat)abstract
- The association between a randomly pyrene labeled PAA polymer (PAAMePy55) and a PEO-PPO-PEO triblock copolymer (P123) in aqueous solutions of different NaCl concentrations and pHs has been studied by means of dynamic light scattering (DLS) and steady-state fluorescence spectroscopy at 40 °C. At acidic pH values, in the low P123/PAAMePy55 molar ratio regime (i.e., at low P123 concentrations), the relaxation time distributions retrieved from the DLS data analysis were monomodal and very similar to those obtained for the pure PAAMePy55 solution. The apparent hydrodynamic radius of PAAMePy55 at low pH is 18 nm. At higher molar ratios (i.e., at high P123 concentrations), still in the acidic pH regime, bimodal relaxation time distributions were obtained, where the fast relaxation mode is connected to the translational diffusion of free P123 micelles with a hydrodynamic radius obtained at infinite P123 dilution (RH,P123)0) of 10-11 nm. This value coincides perfectly with the hydrodynamic radius of the pure P123 micelles at 40 °C, which was found to be ca. 10 nm at all pH values. The second mode corresponds to a complex consisting of one PAAMePy55 polymer chain and about 42 P123 micelles and with a RH,P123)0 between 35 and 36 nm depending on pH. At pH 9, the mixed system also presented bimodal relaxation time distributions. At this high pH, the intermolecular association between PAAMePy55 and P123 is less strong than at acidic pH according to the steady-state fluorescence measurements. The fast mode is also in this case attributed to free P123 micelles whereas the second mode is related to the so-called “slow mode” commonly observed for polyelectrolyte solutions. In this system, it is related to the formation of multichain domains, that is, large domains formed by several PAAMePy55 chains that move in a common electrostatic field (i.e., a structure factor effect). The presence of P123 micelles does not lead to the total disruption of these domains. They may either contain entrapped P123 micelles or hydrophilic diblock impurities (originating from the P123 sample) that associate with the PAAMePy55 chains.
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