| 1. |
- Chantzi, Efthymia, et al.
(författare)
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COMBSecretomics : a pragmatic methodological framework for higher-order drug combination analysis using secretomics
- 2020
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:5
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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.
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| 2. |
- Chantzi, Efthymia
(författare)
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Algorithmic discovery, development and personalized selection of higher-order drug cocktails : A label-free live-cell imaging & secretomics approach
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- An upward trend in clinical pharmacology is the use of multiple drugs to combat complex and co-occurring diseases due to better efficacy, decreased toxicity and reduced risk of evolving resistance. Despite high late-stage attrition rates and the need for multi drug treatments, most drug discovery and development efforts are still mainly focused on new one-size-fits-all monotherapies. This is unfortunate given the complex, heterogeneous and often only partially understood pathophysiology of many diseases. In this context, polypharmacotherapies hold strong potential, especially when patient tailored. However, as of today, the personalized combination therapy area remains vastly unexplored. A major reason is lack of standardized and robust tools that allow systematic in vitro drug combination sensitivity testing of different disease models and patient derived cells.This thesis fills in this lack by introducing two methodological frameworks, namely COMBImageDL and COMBSecretomics, designed to enable systematic second- and higher-order drug combination studies within and beyond cancer pharmacology. They include advanced quality control procedures, non-parametric resampling statistics to quantify uncertainty and a data driven methodology to evaluate response patterns and discern higher- from lower- and single-drug effects. Both are based on a standardized and reproducible format that could be employed with any experimental platform that provides the required raw data. COMBImageDL searches exhaustively for drug cocktails that induce changes in cell viability and time evolving cell culture morphology by employing conventional endpoint synergy analyses jointly with quantitative label-free live-cell imaging. Deep neural network learning, MapReduce parallel processing and method-specific parameter tuning are key components of the design. The purely phenotypic functionality of COMBImageDL is extended by COMBSecretomics, which searches exhaustively for drug cocktails that can modify, or even reverse malfunctioning secretomic patterns. It processes complex datasets involving drug treated cells observed before and after being stimulated by relevant proteins. Finally, the highest single agent method is generalized for higher-order drug combination analysis and adjusted for secreted protein profiles.The frameworks were used in five pharmacological studies being industrial, academic and clinical collaborations in areas where novel and personalized multi drug regimens are highly needed; oncology (acute myeloid leukemia and glioblastoma multiforme) and osteoarthritis. These studies demonstrate intriguing drug combination findings and in general the great potential of tools like COMBImageDL and COMBSecretomics to accelerate the discovery and development of novel potent polypharmacotherapeutic candidates.
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| 3. |
- Jash, Asmita, et al.
(författare)
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Time-resolved photoluminescence studies of single interface wurtzite/zincblende heterostructured InP nanowires
- 2022
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 120:11
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Tidskriftsartikel (refereegranskat)abstract
- The interface between wurtzite and zinc blende InP has been identified as type-II, where electrons gather on the zinc blende side and holes on the wurtzite side of the interface. The photoluminescence resulting from recombination across the interface is expected to be long-lived and to exhibit non-exponential decay of emission intensity after pulsed excitation. We verify this prediction using time-resolved photoluminescence spectroscopy on nanowires containing a single heterostructure between a single segment of wurtzite and zinc blende. We find that a significant intensity of type-II emission remains even more than 30 ns after excitation. The decay of the emission intensity is also non-exponential and considerably longer than the exponential decay of the wurtzite InP segment (260 ps). Our results are consistent with the expected photoluminescence characteristics of a type-II interface between the two polytypes. We also find that the lifetime becomes shorter if we create an electron gas at the interface by n-type doping the entire wurtzite segment of the nanowire. This is expected since there are many electrons that a given hole can recombine with, in contrast to the undoped case.
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| 4. |
- Ludvig-Osipov, Andrei, et al.
(författare)
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Fundamental Bounds on Transmission Through Periodically Perforated Metal Screens With Experimental Validation
- 2020
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Ingår i: IEEE Transactions on Antennas and Propagation. - : IEEE. - 0018-926X .- 1558-2221. ; 68:2, s. 773-782
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Tidskriftsartikel (refereegranskat)abstract
- This article presents a study of transmission through arrays of periodic sub-wavelength apertures. Fundamental limitations for this phenomenon are formulated as a sum rule, relating the transmission coefficient over a bandwidth to the static polarizability. The sum rule is rigorously derived for arbitrary periodic apertures in thin screens. By this sum rule we establish a physical bound on the transmission bandwidth which is verified numerically for a number of aperture array designs. We utilize the sum rule to design and optimize sub-wavelength frequency selective surfaces with a bandwidth close to the physically attainable. Finally, we verify the sum rule and simulations by measurements of an array of horseshoe-shaped slots milled in aluminum foil.
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| 5. |
- Nedic, Mitja, et al.
(författare)
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Herglotz functions and applications in electromagnetics
- 2020
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Ingår i: Advances in Mathematical Methods for Electromagnetics. - : Institution of Engineering and Technology. - 9781785613845 - 9781785613852 ; , s. 491-514
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Herglotz functions inevitably appear in pure mathematics, mathematical physics, and engineering with a wide range of applications. In particular, they are the pertinent functions to model passive systems, and thus appear in modeling of electromagnetic phenomena in circuits, antennas, materials, and scattering. In this chapter, we review the basic theory of Herglotz functions and its applications to determine sum rules and physical bounds for passive systems.
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| 6. |
- Neidlin, Michael, et al.
(författare)
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A Novel Multiplex Based Platform for Osteoarthritis Drug Candidate Evaluation
- 2020
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Ingår i: Annals of Biomedical Engineering. - : Springer Science and Business Media LLC. - 0090-6964 .- 1573-9686. ; 48:10, s. 2438-2448
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Tidskriftsartikel (refereegranskat)abstract
- Osteoarthritis (OA) is characterized by irreversible cartilage degradation with very limited therapeutic interventions. Drug candidates targeted at prototypic players had limited success until now and systems based approaches might be necessary. Consequently, drug evaluation platforms should consider the biological complexity looking beyond well-known contributors of OA. In this study an ex vivo model of cartilage degradation, combined with measuring releases of 27 proteins, was utilized to study 9 drug candidates. After an initial single drug evaluation step the 3 most promising compounds were selected and employed in an exhaustive combinatorial experiment. The resulting most and least promising treatment candidates were selected and validated in an independent study. This included estimation of mechanical properties via finite element modelling (FEM) and quantification of cartilage degradation as glycosaminoglycan (GAG) release. The most promising candidate showed increase of Young’s modulus, decrease of hydraulic permeability and decrease of GAG release. The least promising candidate exhibited the opposite behaviour. The study shows the potential of a novel drug evaluation platform in identifying treatments that might reduce cartilage degradation. It also demonstrates the promise of exhaustive combination experiments and a connection between chondrocyte responses at the molecular level with changes of biomechanical properties at the tissue level.
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