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- Allesøe, Rosa Lundbye, et al.
(författare)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Tidskriftsartikel (refereegranskat)abstract
- The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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- Facon, T, et al.
(författare)
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Daratumumab plus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: frailty subgroup analysis of MAIA
- 2022
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 36:4, s. 1066-1077
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Tidskriftsartikel (refereegranskat)abstract
- In the phase 3 MAIA study of patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab plus lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd). We present a subgroup analysis of MAIA by frailty status. Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit, intermediate, non-frail (fit + intermediate), or frail. Of the randomized patients (D-Rd, n = 368; Rd, n = 369), 396 patients were non-frail (D-Rd, 196 [53.3%]; Rd, 200 [54.2%]) and 341 patients were frail (172 [46.7%]; 169 [45.8%]). After a 36.4-month median follow-up, non-frail patients had longer PFS than frail patients, but the PFS benefit of D-Rd versus Rd was maintained across subgroups: non-frail (median, not reached [NR] vs 41.7 months; hazard ratio [HR], 0.48; P < 0.0001) and frail (NR vs 30.4 months; HR, 0.62; P = 0.003). Improved rates of complete response or better and minimal residual disease (10–5) negativity were observed for D-Rd across subgroups. The most common grade 3/4 treatment-emergent adverse event in non-frail and frail patients was neutropenia (non-frail, 45.4% [D-Rd] and 37.2% [Rd]; frail, 57.7% and 33.1%). These findings support the clinical benefit of D-Rd in transplant-ineligible NDMM patients enrolled in MAIA, regardless of frailty status.
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- San-Miguel, J, et al.
(författare)
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Subcutaneous daratumumab in patients with relapsed or refractory multiple myeloma: Part 2 of the open-label, multicenter, dose-escalation phase 1b study (PAVO)
- 2021
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 106:6, s. 1725-1732
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Tidskriftsartikel (refereegranskat)abstract
- Intravenous daratumumab is approved for the treatment of multiple myeloma. In Part 1 of the PAVO study, a mix-and-deliver subcutaneous formulation of daratumumab with recombinant human hyaluronidase PH20 (rHuPH20) was well tolerated, with low rates of infusion-related reactions and similar efficacy to intravenous daratumumab. Part 2 of PAVO evaluated a concentrated, pre-mixed co-formulation of daratumumab and rHuPH20 (DARA SC). Patients with ≥2 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, received daratumumab (1800 mg) and rHuPH20 (30,000 U) in 15 mL subcutaneously over 3-5 minutes per the approved intravenous monotherapy dosing schedule. Primary endpoints were daratumumab trough concentration at the end of weekly dosing (just prior to the Cycle 3 Day 1 dose) and safety. Twenty-five patients were enrolled in PAVO Part 2. DARA SC achieved daratumumab trough concentrations similar to or greater than intravenous daratumumab 16 mg/kg. The adverse event profile of DARA SC was consistent with intravenous daratumumab, with no new safety concerns and a lower infusion-related reaction rate. At a median follow-up of 14.2 months, the overall response rate was 52%, median duration of response was 15.7 months, and median progression-free survival was 12.0 months. DARA SC 1800 mg was well tolerated in relapsed/refractory multiple myeloma, with a low infusion-related reaction rate and reduced administration time. Daratumumab serum concentrations following DARA SC were consistent with intravenous dosing, and deep and durable responses were observed. Based on these results, ongoing studies are investigating DARA SC in multiple myeloma and other conditions. (ClinicalTrials.gov identifier: 02519452).
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- Gulbrandsen, I. T., et al.
(författare)
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New Media and Strategy Research: Towards a Relational Agency Approach
- 2020
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Ingår i: International Journal of Management Reviews. - : Wiley. - 1460-8545 .- 1468-2370. ; 22:1, s. 33-52
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Tidskriftsartikel (refereegranskat)abstract
- A rapidly growing body of literature focuses on the relationship between new media and strategy, and offers recommendations regarding appropriate strategic actions in relation to new media. This paper systematically reviews 130 articles with a focus on the diagnoses they provide and the directions they offer strategists regarding the role of new media in strategy. The analysis identifies four main ways of conceptualizing new media in the literature: as forces in an increasingly turbulent strategic environment; as changing the role of strategists; as tools for strategically engaging stakeholders; and as both increasing and decreasing the control necessary for strategy making. These conceptualizations are based on often-implicit assumptions about 'agency' in strategy: new media are seen either as forces influencing strategy or as tools in the hands of humans, who are portrayed as the agents of strategy. In both cases, new media are black-boxed, such that their specific properties and ways of becoming embedded in particular contexts are rarely examined. After discussing these assumptions and a limited number of studies that challenge them, the paper develops an approach to strategy and new media based on a relational understanding of agency, an attention to technological affordances and a methodological sensitivity to tracing strategy-making assemblages of human and non-human elements. We argue that future research based on this approach will advance our knowledge of strategy making in ways that do not take new media for granted and ways that are attentive to different kinds of agency.
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