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Johansen, P.

Publications and source records attributed to Johansen, P..

3 recordsLinked to original sources

Aortic annuloplasty FSI digital twin of 3D-printed phantoms with 4D-flow MRI comparison

BackgroundAortic annuloplasty, involving the implantation of an external ring around the aortic root to reduce annular dimensions, is a promising treatment for aortic valve insufficiency. However, its hemodynamic effects remain underexplored due to the absence of computational models validated by experimental and clinical data. MethodsThis study introduces a computational fluid-structure interaction (FSI) model of supra valvular aortic annuloplasty using 4D-flow magnetic resonance imaging (MRI). Native and post-annuloplasty conditions of idealized aortic root phantoms, including the aortic valve, were CAD-modelled and 3D-printed with elastic resin. These phantoms were tested in a mock circulatory flow-loop providing normal pulsatile physiologic conditions using a glycerol-water mixture to simulate blood viscosity. Flow and pressure data collected from sensors were used as boundary conditions for FSI simulations. Experimental velocity fields from 4D-flow MRI were compared to computational results to assess model accuracy. ResultsMRI scans of the annuloplasty model showed an increased peak systolic velocity (up to 145.4 cm/s) and localized flow alterations, corresponding to a higher pressure gradient across the valve. During regurgitation, the annuloplasty model showed broader velocity distributions compared to the native condition. The FSI simulations closely matched 4D-flow MRI data, with strong correlation coefficients (r > 0.93) and minimal Bland-Altman differences, particularly during systolic phases. ConclusionsThis study establishes an integrative methodology combining in-vitro, in-silico, and clinical imaging techniques to evaluate aortic annuloplasty hemodynamics. The validated digital twin framework offers a pathway for patient-specific modelling, enabling prediction of surgical outcomes and optimization of aortic valve repair strategies.

bioengineering↗

ROS induction as a strategy to target persister cancer cells with low metabolic activity in NRAS mutated melanoma

Metabolic reprogramming is an emerging hallmark of resistance to cancer therapy but may generate vulnerabilities that can be targeted with small molecules. Multi-omics analysis revealed that NRAS-mutated melanoma cells with a mesenchymal transcriptional profile adopt a quiescent metabolic program to resist cellular stress response induced by MEK-inhibitor resistance. However, as a result of elevated baseline ROS levels, these cells become highly sensitive to ROS induction. In vivo xenograft experiments and single-cell RNA sequencing demonstrated that intra-tumor heterogeneity requires the combination of a ROS-inducer and a MEK-inhibitor to target both tumor growth and metastasis. By ex vivo pharmacoscopy of 62 human metastatic melanomas, we found that MEK-inhibitor resistant tumors significantly benefitted from the combination therapy. Finally, we profiled 486 cancer cell lines and revealed that oxidative stress responses and translational suppression are biomarkers of ROS-inducer sensitivity, independent of cancer indication. These findings link transcriptional plasticity to a metabolic phenotype that can be inhibited by ROS-inducers in melanoma and other cancers. Statement of SignificanceTargeted-therapy resistance in cancer arises from genetic selection and both transcriptional and metabolic adaptation. We show that metabolic reprogramming sensitizes resistant cells to ROS-induction in combination with pathway inhibitors. Predictive biomarkers of metabolic sensitivity to ROS-inducing agents were identified in many cancer entities, highlighting the generalizability of this treatment approach. Graphical summary O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

cancer biology↗

Method to identify physical, chemical and biological factors that trigger Bcl-xL-mediated apoptosis

The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. Here, we show that Bcl-xL-specific agent A-1155463 prematurely kills cells of different origins and the small roundworms (C. elegans), when combined with DNA-damaging agent 4-nitroquinoline-1-oxide (4NQO). The synergistic effect of 4NQO-A-1155463 combination was p53-dependent, was associated with the release of Bad and Bax from Bcl-xL, which triggered mitochondrial outer membrane permeabilization (MOMP). Combinations of Bcl-xL-specific inhibitors with certain anticancer compounds or physical insults also killed cells. Collectively, our results suggest that biological, chemical and physical factors trigger evolutionary conserved Bcl-xL-mediated apoptotic pathway.

cancer biology↗