| 1. |
- Aad, G, et al.
(författare)
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- 2015
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swepub:Mat__t
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| 2. |
- Menden, MP, et al.
(författare)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Tidskriftsartikel (refereegranskat)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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| 3. |
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| 4. |
- Lin, C., et al.
(författare)
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Velocity characteristics in boundary layer flow caused by solitary wave traveling over horizontal bottom
- 2016
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Ingår i: Experimental Thermal and Fluid Science. - : Elsevier. - 0894-1777 .- 1879-2286. ; 76, s. 238-252
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Tidskriftsartikel (refereegranskat)abstract
- The characteristics of horizontal velocity in the bottom boundary-layer flow induced by a solitary wave propagating over a horizontal bottom are presented experimentally, using high-speed particle image velocimetry (HSPIV). The ratio of wave height to water depth varies from 0.096 to 0.386 and the flow inside the boundary layer is laminar. The results show that the horizontal velocity profiles can be mainly classified into two categories with respect to the passing of the solitary wave-crest at the measuring section: the pre-passing (or acceleration) phases under favorable pressure gradient and post-passing (or deceleration) phases under adverse pressure gradient. For the velocity distributions obtained during the pre-passing phases, a nonlinear regression analysis was used to precisely determine the time-dependent characteristic length and velocity scales underlying these profiles. A similarity profile of the horizontal velocity is established first using the time-dependent free-stream velocity and boundary layer thickness as the characteristic velocity and length scales, respectively. In addition, the displacement thickness, the momentum thickness, and the energy thickness are also considered as alternative length scales. All these four representative thicknesses are closely related to each other, demonstrating that any one amongst them can be regarded as the characteristic length scale. The forms of similarity profiles for the non-dimensional velocity distributions are somewhat analogous to the results of steady boundary layer flow over a thin plate under with pressure gradient, but with different coefficients or powers. While during the post-passing phases, flow reversal which acts like an unsteady wall jet and moves in the opposite direction against the wave propagation occurs after the passage of solitary wave-crest. The thickness of flow reversal layer increases with time. A similarity profile is proposed for the velocity distributions corresponding to occurrence of the extreme value in the maximum negative velocity of flow reversal. Variations of the maximum negative velocity and the thickness of flow reversal with the time right after the start of flow reversal are also discussed in detail. Moreover, the non-dimensional time leads of the horizontal velocities at different heights in the boundary layer over the free-stream velocity are evidenced to be more noticeable toward the bottom, and also in lower ratio of wave height to water depth. A similarity profile for the non-dimensional time lead versus the non-dimensional height above the bottom surface is also presented.
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| 5. |
- Ben-Akiva, Elana, et al.
(författare)
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Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination
- 2023
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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 (PNAS). - 0027-8424 .- 1091-6490. ; 120:26
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Tidskriftsartikel (refereegranskat)abstract
- Nanoparticle (NP) -based mRNA cancer vaccines hold great promise to realize person-alized cancer treatments. To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta- amino ester) nanocarriers with quadpolymer architec-ture. The platform is agnostic to the mRNA sequence, with one -step self-assembly allow-ing for delivery of multiple antigen-encoding mRNAs as well as codelivery of nucleic acid-based adjuvants. We examined structure-function relationships for NP-mediated mRNA delivery to dendritic cells (DCs) and identified that a lipid subunit of the pol-ymer structure was critical. Following intravenous administration, the engineered NP design facilitated targeted delivery to the spleen and preferential transfection of DCs without the need for surface functionalization with targeting ligands. Treatment with engineered NPs codelivering antigen-encoding mRNA and toll -like receptor agonist adjuvants led to robust antigen-specific CD8+ T cell responses, resulting in efficient antitumor therapy in in vivo models of murine melanoma and colon adenocarcinoma.
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| 6. |
- Karlsson, Johan, et al.
(författare)
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Nanoparticle designs for delivery of nucleic acid therapeutics as brain cancer therapies.
- 2021
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Ingår i: Advanced Drug Delivery Reviews. - : Elsevier BV. - 0169-409X .- 1872-8294. ; 179, s. 113999-
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) is an aggressive central nervous system cancer with a dismal prognosis. The standard of care involves surgical resection followed by radiotherapy and chemotherapy, but five-year survival is only 5.6% despite these measures. Novel therapeutic approaches, such as immunotherapies, targeted therapies, and gene therapies, have been explored to attempt to extend survival for patients. Nanoparticles have been receiving increasing attention as promising vehicles for non-viral nucleic acid delivery in the context of GBM, though delivery is often limited by low blood-brain barrier permeability, particle instability, and low trafficking to target brain structures and cells. In this review, nanoparticle design considerations and new advances to overcome nucleic acid delivery challenges to treat brain cancer are summarized and discussed.
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| 7. |
- Karlsson, Johan, 1979-, et al.
(författare)
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Photocrosslinked Bioreducible Polymeric Nanoparticles for Enhanced Systemic siRNA Delivery as Cancer Therapy
- 2021
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Ingår i: Advanced Functional Materials. - : John Wiley & Sons. - 1616-301X .- 1616-3028. ; 31:17
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Tidskriftsartikel (refereegranskat)abstract
- Clinical translation of polymer-based nanocarriers for systemic delivery of RNA has been limited due to poor colloidal stability in the blood stream and intracellular delivery of the RNA to the cytosol. To address these limitations, this study reports a new strategy incorporating photocrosslinking of bioreducible nanoparticles for improved stability extracellularly and rapid release of RNA intracellularly. In this design, the polymeric nanocarriers contain ester bonds for hydrolytic degradation and disulfide bonds for environmentally triggered small interfering RNA (siRNA) release in the cytosol. These photocrosslinked bioreducible nanoparticles (XbNPs) have a shielded surface charge, reduced adsorption of serum proteins, and enable superior siRNA-mediated knockdown in both glioma and melanoma cells in high-serum conditions compared to non-crosslinked formulations. Mechanistically, XbNPs promote cellular uptake and the presence of secondary and tertiary amines enables efficient endosomal escape. Following systemic administration, XbNPs facilitate targeting of cancer cells and tissue-mediated siRNA delivery beyond the liver, unlike conventional nanoparticle-based delivery. These attributes of XbNPs facilitate robust siRNA-mediated knockdown in vivo in melanoma tumors colonized in the lungs following systemic administration. Thus, biodegradable polymeric nanoparticles, via photocrosslinking, demonstrate extended colloidal stability and efficient delivery of RNA therapeutics under physiological conditions, and thereby potentially advance systemic delivery technologies for nucleic acid-based therapeutics.
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