| 1. |
- Michaut, Magali, et al.
(författare)
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Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer.
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.
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| 2. |
- Bassani, Carlos L., et al.
(författare)
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Nanocrystal Assemblies : Current Advances and Open Problems
- 2024
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Ingår i: ACS Nano. - 1936-0851. ; 18:23, s. 14791-14840
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Forskningsöversikt (refereegranskat)abstract
- We explore the potential of nanocrystals (a term used equivalently to nanoparticles) as building blocks for nanomaterials, and the current advances and open challenges for fundamental science developments and applications. Nanocrystal assemblies are inherently multiscale, and the generation of revolutionary material properties requires a precise understanding of the relationship between structure and function, the former being determined by classical effects and the latter often by quantum effects. With an emphasis on theory and computation, we discuss challenges that hamper current assembly strategies and to what extent nanocrystal assemblies represent thermodynamic equilibrium or kinetically trapped metastable states. We also examine dynamic effects and optimization of assembly protocols. Finally, we discuss promising material functions and examples of their realization with nanocrystal assemblies.
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| 3. |
- Bunyapaiboonsri, T., et al.
(författare)
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Dynamic deconvolution of a pre-equilibrated dynamic combinatorial library of acetylcholinesterase inhibitors
- 2001
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Ingår i: ChemBioChem. - 1439-4227 .- 1439-7633. ; 2:6, s. 438-444
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Tidskriftsartikel (refereegranskat)abstract
- A dynamic combinatorial library composed of interconverting acylhydrazones has been generated and screened towards inhibition of acetylcholinesterase from the electric ray Torpedo marmorata. Starting from a small set (13) of initial hydrazide and aldehyde building blocks, a library containing possibly 66 different species was obtained in a single operation. Of all possible acylhydrazones formed, active compounds containing two terminal cationic recognition groups separated by an appropriate distance, permitting two-site binding, could be rapidly identified by using a dynamic deconvolution-screening procedure, based on the sequential removal of starting building blocks. A very potent bis-pyridinium inhibitor (K (i)= 1.09 nM, alphaK(i) = 2.80 nM) was selected from the process and the contribution of various structural features to inhibitory potency was evaluated.
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| 4. |
- Bunyapaiboonsri, T., et al.
(författare)
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Generation of Bis-cationic heterocyclic inhibitors of Bacillus subtilis HPr kinase/phosphatase from a ditopic dynamic combinatorial library
- 2003
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 46:26, s. 5803-5811
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Tidskriftsartikel (refereegranskat)abstract
- Ditopic dynamic combinatorial. libraries were generated and screened toward inhibition of the bifunctional enzyme HPr kinase/phosphatase from Bacillus subtilis. The libraries were composed of all possible combinations resulting from the dynamic interconversion of 16 hydrazides and five monoaldehyde or dialdehyde building blocks, resulting in libraries containing up to 440 different constituents. Of all possible acyl hydrazones formed, active compounds containing two terminal cationic heterocyclic recognition groups separated by a spacer of appropriate structure could be rapidly identified using a dynamic deconvolution procedure. Thus, parallel testing of sublibraries where one specific component was excluded basically revealed all the essential components. A potent ditopic inhibitor, based on 2-amino-benzimidazole, was identified from the process.
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| 5. |
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| 6. |
- Pei, Zhichao, et al.
(författare)
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Quartz crystal microbalance bioaffinity sensor for rapid identification of glycosyldisulfide lectin inhibitors from a dynamic combinatorial library
- 2006
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Ingår i: Biosensors & bioelectronics. - : Elsevier BV. - 0956-5663 .- 1873-4235. ; 22:1, s. 42-48
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Tidskriftsartikel (refereegranskat)abstract
- Carbohydrate-lectin,interactions were probed with dynamic combinatorial libraries, using the plant lectin Concanavalin A as target species. The dynamic combinatorial libraries were generated from a pool of thiol components through reversible thiol-disulfide interchange, and screened using a simple and efficient method based on a quartz crystal microbalance setup. It was found that dimers based on 1-thio- and 6-thin-mannose analogues were the most active inhibitors. Furthermore, the results clearly show that the 6-thio-mannose possess unique characteristics compared to its oxygen-containing counterpart.
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| 7. |
- Ramström, Olof, et al.
(författare)
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Chemical biology of dynamic combinatorial libraries
- 2002
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Ingår i: Biochimica et Biophysica Acta - General Subjects. - 0304-4165 .- 1872-8006. ; 1572:03-feb, s. 178-186
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Forskningsöversikt (refereegranskat)abstract
- Dynamic combinatorial chemistry (DCC) is a recently introduced supramolecular approach to generate libraries of chemical compounds based on reversible exchange processes. The building elements are spontaneously and reversibly assembled to virtually encompass all possible combinations, allowing for simple one-step generation of complex libraries. The method has been applied to a variety of combinatorial systems, ranging from synthetic models to materials science and drug discovery, and enables the establishment of adaptive processes due to the dynamic interchange of the library constituents and its evolution toward the best fit to the target. In particular, it has the potential to become a useful tool in the direct screening of ligands to a chosen receptor without extensive prior knowledge of the site structure, and several biological systems have been targeted. In the vast field of glycoscience, the concept may find special perspective in response to the highly complex nature of carbohydrate-protein interactions. This chapter summarises studies that have been performed using DCC in biological systems, with special emphasis on glycoscience.
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| 8. |
- Ramström, Olof, et al.
(författare)
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Drug discovery by dynamic combinatorial libraries
- 2002
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Ingår i: Nature reviews. Drug discovery. - : Springer Science and Business Media LLC. - 1474-1776 .- 1474-1784. ; 1:1, s. 26-36
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Forskningsöversikt (refereegranskat)abstract
- Dynamic combinatorial chemistry is a recently introduced supramolecular approach that uses self-assembly processes to generate libraries of chemical compounds. In contrast to the stepwise methodology of classical combinatorial techniques, dynamic combinatorial chemistry allows for the generation of libraries based on the continuous interconversion between the library constituents. Spontaneous assembly of the building blocks through reversible chemical reactions virtually encompasses all possible combinations, and allows the establishment of adaptive processes owing to the dynamic interchange of the library constituents. Addition of the target ligand or receptor creates a driving force that favours the formation of the best-binding constituent - a self-screening process that is capable, in principle, of accelerating the identification of lead compounds for drug discovery.
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| 9. |
- Ramström, Olof, et al.
(författare)
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Dynamic combinatorial carbohydrate libraries : Probing the binding site of the concanavalin A lectin
- 2004
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Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 10:7, s. 1711-1715
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Tidskriftsartikel (refereegranskat)abstract
- Dynamic combinatorial chemistry (DCC) has emerged as an efficient approach to receptor/ligand identification based on the generation of combinatorial libraries by reversible interconversion of the library constituents. In this study, the implementation of such libraries on carbohydrate-lectin interactions was examined with the plant lectin Concanavalin A as a target species. Dynamic carbohydrate libraries were generated from a pool of carbohydrate aldehydes and hydrazide linker/scaffold components through re- versible acylhydrazone exchange, resulting in libraries containing up to 474 constituents. Dynamic deconvolution allowed the efficient identification of the structural features required for binding to Concanavalin A and the selection of a strong binder, a tritopic mannoside, showing an IC50-value of 22 mum.
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| 10. |
- Ramström, Olof, et al.
(författare)
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In situ generation and screening of a dynamic combinatorial carbohydrate library against concanavalin A
- 2000
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Ingår i: ChemBioChem. - 1439-4227 .- 1439-7633. ; 1:1, s. 41-48
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Tidskriftsartikel (refereegranskat)abstract
- Dynamic combinatorial chemistry (DCC) is a recently introduced approach that is based on the generation of combinatorial libraries by reversible interconversion of the library constitutents. In this study, the implementation of such libraries on carbohydrate-lectin interactions was examined. The dynamic carbohydrate libraries were generated from a small set (four or six compounds) of initial carbohydrate dimers through mild disulfide interchange, and selection was performed under two conditions defining either adaptive or pre-equilibrated libraries. Upon initiation, libraries were formed that contained comparable amounts of 10 or 21 individual dimeric species, dynamically interchanging during the scrambling process. They were probed with respect to binding to the plant lectin concanavalin A, either present during library generation or added after equilibration. The libraries could be generated easily both in the presence and absence of the receptor, and a bis-mannose structure was preferentially bound and selected from the mixture. Scrambling of the library in the presence of the receptor resulted in slightly higher yields than when the receptor was added after scrambling, indicating that the receptor to some extent acts as a thermodynamic trap during library generation. The present results illustrate the extention of the DCC approach to carbohydrate recognition groups, the generation of isoenergetic dynamic libraries, and the implementation of either adaptive or pre-equilibrated procedures.
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