| 441. |
- de Kloe, Gerdien E, et al.
(författare)
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Surface Plasmon Resonance Biosensor Based Fragment Screening Using Acetylcholine Binding Protein Identifies Ligand Efficiency Hot Spots (LE Hot Spots) by Deconstruction of Nicotinic Acetylcholine Receptor α7 Ligands
- 2010
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:19, s. 7192-7201
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Tidskriftsartikel (refereegranskat)abstract
- The soluble acetylcholine binding protein (AChBP) is a homologue of the ligand-binding domain of the nicotinic acetylcholine receptors (nAChR). To guide future fragment-screening using surface plasmon resonance (SPR) biosensor technology as a label-free, direct binding, biophysical screening assay, a focused fragment library was generated based on deconstruction of a set of α7 nAChR selective quinuclidine containing ligands with nanomolar affinities. The interaction characteristics of the fragments and the parent compounds with AChBP were evaluated using an SPR biosensor assay. The data obtained from this direct binding assay correlated well with data from the reference radioligand displacement assay. Ligand efficiencies for different (structural) groups of fragments in the library were correlated to binding with distinct regions of the binding pocket, thereby identifying ligand efficiency hot spots (LE hot spots). These hot spots can be used to identity the most promising hit fragments in a large scale fragment library screen.
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| 442. |
- Delfin, Carl, et al.
(författare)
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A Federated Database for Obesity Research : An IMI-SOPHIA Study
- 2024
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Ingår i: Life. - 0024-3019. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is considered by many as a lifestyle choice rather than a chronic progressive disease. The Innovative Medicines Initiative (IMI) SOPHIA (Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy) project is part of a momentum shift aiming to provide better tools for the stratification of people with obesity according to disease risk and treatment response. One of the challenges to achieving these goals is that many clinical cohorts are siloed, limiting the potential of combined data for biomarker discovery. In SOPHIA, we have addressed this challenge by setting up a federated database building on open-source DataSHIELD technology. The database currently federates 16 cohorts that are accessible via a central gateway. The database is multi-modal, including research studies, clinical trials, and routine health data, and is accessed using the R statistical programming environment where statistical and machine learning analyses can be performed at a distance without any disclosure of patient-level data. We demonstrate the use of the database by providing a proof-of-concept analysis, performing a federated linear model of BMI and systolic blood pressure, pooling all data from 16 studies virtually without any analyst seeing individual patient-level data. This analysis provided similar point estimates compared to a meta-analysis of the 16 individual studies. Our approach provides a benchmark for reproducible, safe federated analyses across multiple study types provided by multiple stakeholders.
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| 443. |
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| 444. |
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| 445. |
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| 446. |
- Enajat, Morteza, et al.
(författare)
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The deep inferior epigastric artery perforator flap for autologous reconstruction of large partial mastectomy defects
- 2011
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Ingår i: Microsurgery. - : Wiley. - 0738-1085 .- 1098-2752. ; 31:1, s. 12-17
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Tidskriftsartikel (refereegranskat)abstract
- Background: Breast conservation surgery in the treatment of early stage breast cancer has become increasingly utilized as a means to avoiding mastectomy. While partial mastectomy defects (PMDs) may often be cosmetically acceptable, some cases warrant consideration of reconstructive options, and while several reconstructive options have been described in this role, a series of deep inferior epigastric perforator (DIEP) flaps has not been reported to date. Methods: A cohort of 18 patients undergoing PMD reconstruction with a DIEP flap were included. Patient-specific data, operation details, cosmetic results, and complication rates were assessed. Oncologic outcomes, in particular recurrence rates, were also evaluated. Results: In our series there were no cases of partial or total flap necrosis, and overall complications were low. There were two cases of wound infection (both had undergone radiotherapy), managed conservatively, and one case of reoperation due to hematoma. There were no cancer recurrences or effect on oncologic management. Cosmetic outcome was rated as high by both patients and surgeon. The results were thus comparable with other reconstructive options. Conclusion: Although autologous reconstruction has an established complication rate, our results suggest that the DIEP flap may be of considerable value for delayed reconstruction of selected larger partial mastectomy defects.
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| 447. |
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| 448. |
- Geelen, Inge G. P., et al.
(författare)
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Switching from imatinib to nilotinib plus pegylated interferon-α2b in chronic phase CML failing to achieve deep molecular response : clinical and immunological effects
- 2023
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Ingår i: Annals of Hematology. - : Springer. - 0939-5555 .- 1432-0584. ; 102:6, s. 1395-1408
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Tidskriftsartikel (refereegranskat)abstract
- In order to improve molecular response for a discontinuation attempt in chronic myeloid leukemia (CML) patients in chronic phase, who had not achieved at least a molecular response <0.01% BCR-ABL1IS (MR4.0) after at least 2 years of imatinib therapy, we prospectively evaluated whether they could attain MR4.0 after a switch to a combination of nilotinib and 9 months of pegylated interferon-α2b (PegIFN). The primary endpoint of confirmed MR4.0 at month 12 (a BCR-ABL1IS level ≤ 0.01% both at 12 and 15 months) was reached by 44% (7/16 patients, 95% confidence interval (CI): 23- 67%) of patients, with 81% (13/16 patients, 95% CI: 57-93%) of patients achieving an unconfirmed MR4.0. The scheduled combination was completed by 56% of the patients, with premature discontinuations, mainly due to mood disturbances after the introduction of PegIFN, questioning the feasibility of the combination of nilotinib and PegIFN for this patient population and treatment goal. A comprehensive clinical substudy program was implemented to characterize the impact of the treatment changes on the immunological profile.
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| 449. |
- Geitmann, Matthis, et al.
(författare)
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Interaction kinetic and structural dynamic analysis of ligand binding to acetylcholine-binding protein
- 2010
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 49:37, s. 8143-8154
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Tidskriftsartikel (refereegranskat)abstract
- The mechanism of agonist interactions with Cys-loop ligand-gated ion channels has been studied using the acetylcholine-binding protein (AChBP) from Lymnaea stagnalis as a model protein, and acetylcholine, nicotine, epibatidine and a series of substituted quinuclidines as ligands. A biosensor-based assay for direct interaction studies of immobilized AChBP and small molecule ligands was developed. It allowed the characterization of the interaction kinetics of the ligands and the structural dynamics of the protein. The interactions with AChBP were very sensitive to variations in the experimental conditions and showed several types of complexities. These could be resolved into two types of ligand-induced secondary effects with different kinetics, representing fast and slow conformational changes. The data could be rationalized in a mechanistic model and a structural interpretation of the interaction was obtained by molecular modelling involving induced-fit and loop flexibility simulations. The data suggests that AChBP exhibits ligand-induced structural dynamics, as expected for the ligand gating mechanism of Cys-loop receptors. It shows that the formation of the initial encounter complex between AChBP and ligands is very rapid, in accordance with the functional characteristics required of neurotransmission. These developed procedures will enable further exploration of the mechanism of Cys-loop receptor function and the identification of specific ligands suitable for pharmacological use.
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| 450. |
- Genereux, Diane P., et al.
(författare)
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A comparative genomics multitool for scientific discovery and conservation
- 2020
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Ingår i: Nature. - : NATURE RESEARCH. - 0028-0836 .- 1476-4687. ; 587:7833, s. 240-245
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Tidskriftsartikel (refereegranskat)abstract
- A whole-genome alignment of 240 phylogenetically diverse species of eutherian mammal-including 131 previously uncharacterized species-from the Zoonomia Project provides data that support biological discovery, medical research and conservation. The Zoonomia Project is investigating the genomics of shared and specialized traits in eutherian mammals. Here we provide genome assemblies for 131 species, of which all but 9 are previously uncharacterized, and describe a whole-genome alignment of 240 species of considerable phylogenetic diversity, comprising representatives from more than 80% of mammalian families. We find that regions of reduced genetic diversity are more abundant in species at a high risk of extinction, discern signals of evolutionary selection at high resolution and provide insights from individual reference genomes. By prioritizing phylogenetic diversity and making data available quickly and without restriction, the Zoonomia Project aims to support biological discovery, medical research and the conservation of biodiversity.
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