| 1. |
- Bocher, Ozvan, et al.
(författare)
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Testing for association with rare variants in the coding and non-coding genome : RAVA-FIRST, a new approach based on CADD deleteriousness score
- 2022
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 18:9, s. e1009923-
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Tidskriftsartikel (refereegranskat)abstract
- Rare variant association tests (RVAT) have been developed to study the contribution of rare variants widely accessible through high-throughput sequencing technologies. RVAT require to aggregate rare variants in testing units and to filter variants to retain only the most likely causal ones. In the exome, genes are natural testing units and variants are usually filtered based on their functional consequences. However, when dealing with whole-genome sequence (WGS) data, both steps are challenging. No natural biological unit is available for aggregating rare variants. Sliding windows procedures have been proposed to circumvent this difficulty, however they are blind to biological information and result in a large number of tests. We propose a new strategy to perform RVAT on WGS data: "RAVA-FIRST" (RAre Variant Association using Functionally-InfoRmed STeps) comprising three steps. (1) New testing units are defined genome-wide based on functionally-adjusted Combined Annotation Dependent Depletion (CADD) scores of variants observed in the gnomAD populations, which are referred to as "CADD regions". (2) A region-dependent filtering of rare variants is applied in each CADD region. (3) A functionally-informed burden test is performed with sub-scores computed for each genomic category within each CADD region. Both on simulations and real data, RAVA-FIRST was found to outperform other WGS-based RVAT. Applied to a WGS dataset of venous thromboembolism patients, we identified an intergenic region on chromosome 18 enriched for rare variants in early-onset patients. This region that was missed by standard sliding windows procedures is included in a TAD region that contains a strong candidate gene. RAVA-FIRST enables new investigations of rare non-coding variants in complex diseases, facilitated by its implementation in the R package Ravages.
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| 2. |
- Kaushik, Suryakant, et al.
(författare)
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Adaptive intensity-modulated proton therapy with 4D robust planning: A dose mimicking approach
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective: A 4D robust optimisation (4DRO) is usually employed when the tumour respiratory motion needs to be addressed. However, it is computationally demanding, and an automated method is preferable for adaptive planning to avoid manual trial-and-error. This study proposes a 4DRO technique based on dose mimicking for adaptive planning.Approach: Initial plans for 4D robust IMPT were created on an average CT (avgCT) for four patients with clinical target volume (CTV) in the lung, oesophagus, or pancreas, respectively. These plans were robustly optimized using three phases of 4DCT and accounting for setup and density uncertainties. Weekly 4DCTs were used for adaptive replanning, using a constant relative biological effectiveness (cRBE) of 1.1. Two methods were used for this purpose: (1) template-based adaptive (TA) planning and (2) dose-mimicking-based adaptive (MA) planning. The plans were evaluated using variable RBE (vRBE) weighted doses and biologically consistent dose accumulation (BCDA).Main results: TA and MA plans had comparable CTV coverage except for one case where MA plan had a higher D98 and D2 but with an increased D2 in an OAR. CTV D98 deviations in non-adaptive plans from the initial plans were up to -7.2% in individual plans and -1.8% when using BCDA. For the OARs, MA plans showed a reduced mean dose and D2 compared to the TA plan, with few exceptions. The vRBE-weighted dose had a mean dose and D2 difference of up to 0.3 Gy and 0.5 Gy, respectively, in the OARs with respect to cRBE-weighted dose.Significance: MA plans indicate better performance in target coverage and OAR dose sparing compared to the TA plans. Moreover, MA method is capable of handling both forms of anatomical variation, namely, changes in density and relative shifts in the position of the OARs.
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| 3. |
- Kaushik, Suryakant, 1993-, et al.
(författare)
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Generation and evaluation of anatomy-preserving virtual CT for online adaptive proton therapy
- 2024
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Ingår i: Medical physics (Lancaster). - 0094-2405. ; 51:3, s. 1536-1546
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Tidskriftsartikel (refereegranskat)abstract
- Background: Daily CTs generated by CBCT correction are required for daily replanning in online-adaptive proton therapy (APT) to effectively deal with inter-fractional changes. Out of the currently available methods, the suitability of a daily CT generation method for proton dose calculation also depends on the anatomical site.Purpose: We propose an anatomy-preserving virtual CT (APvCT) method as a hybrid method of CBCT correction, which is especially suitable for large anatomy deformations. The accuracy of the hybrid method was assessed by comparison with the corrected CBCT (cCBCT) and virtual CT (vCT) methods in the context of online APT.Methods: Seventy-one daily CBCTs of four prostate cancer patients treated with intensity modulated proton therapy (IMPT) were converted to daily CTs using cCBCT, vCT, and the newly proposed APvCT method. In APvCT, planning CT (pCT) were mapped to CBCT geometry using deformable image registration with boundary conditions on controlling regions of interest (ROIs) created with deep learning segmentation on cCBCT. The relative frequency distribution (RFD) of HU, mass density and stopping power ratio (SPR) values were assessed and compared with the pCT. The ROIs in the APvCT and vCT were compared with cCBCT in terms of Dice similarity coefficient (DSC) and mean distance-to-agreement (mDTA). For each patient, a robustly optimized IMPT plan was created on the pCT and subsequent daily adaptive plans on daily CTs. For dose distribution comparison on the same anatomy, the daily adaptive plans on cCBCT and vCT were recalculated on the corresponding APvCT. The dose distributions were compared in terms of isodose volumes and 3D global gamma-index passing rate (GPR) at γ(2%, 2 mm) criterion.Results: For all patients, no noticeable difference in RFDs was observed amongst APvCT, vCT, and pCT except in cCBCT, which showed a noticeable difference. The minimum DSC value was 0.96 and 0.39 for contours in APvCT and vCT respectively. The average value of mDTA for APvCT was 0.01 cm for clinical target volume and ≤0.01 cm for organs at risk, which increased to 0.18 cm and ≤0.52 cm for vCT. The mean GPR value was 90.9%, 64.5%, and 67.0% for APvCT versus cCBCT, vCT versus cCBCT, and APvCT versus vCT, respectively. When recalculated on APvCT, the adaptive cCBCT and vCT plans resulted in mean GPRs of 89.5 ± 5.1% and 65.9 ± 19.1%, respectively. The mean DSC values for 80.0%, 90.0%, 95.0%, 98.0%, and 100.0% isodose volumes were 0.97, 0.97, 0.97, 0.95, and 0.91 for recalculated cCBCT plans, and 0.89, 0.88, 0.87, 0.85, and 0.81 for recalculated vCT plans. Hausdorff distance for the 100.0% isodose volume in some cases of recalculated cCBCT plans on APvCT exceeded 1.00 cm.Conclusions: APvCT contours showed good agreement with reference contours of cCBCT which indicates anatomy preservation in APvCT. A vCT with erroneous anatomy can result in an incorrect adaptive plan. Further, slightly lower values of GPR between the APvCT and cCBCT-based adaptive plans can be explained by the difference in the cCBCT's SPR RFD from the pCT.
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| 4. |
- Kaushik, Suryakant
(författare)
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Robust optimization considering uncertainties in adaptive proton therapy.
- 2024
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Proton therapy, a promising alternative to conventional photon therapy, has gained widespread acceptance in clinical practice. This is attributed to its superior depth-dose curve that has a negligible dose beyond the maximum range of the proton. A proton treatment planning requires a multitude of parameters and are either manually selected or optimized using mathematical formulation. However, a proton treatment plan is also subject to various systematic and random uncertainties that must be taken into account during optimization. Robust optimization is a commonly used method for integrating the setup and range uncertainties in proton therapy.In addition to the uncertainties accounted for during the treatment planning phase, others can arise during the course of treatment and are often hard to predict. Changes in the patient's anatomy represent uncertainties that can significantly affect planned dose delivery. Therefore, adaptive planning is typically performed intermittently or regularly, depending on the changes in anatomy. Paper II included in this thesis proposed a method of adaptive planning that takes into account the impact of the patient's respiratory motion at the treatment site, such as the lungs and abdomen for 4D robust optimization. This method uses dose mimicking to reproduce the results as initially planned. This additional stage of adaptive planning can introduce new complexities and uncertainties into the treatment process. One such uncertainty arise from daily cone beam computed tomography (CBCT) images which are required for treatment plan adaptation. Several strategies have been proposed in the past to improve the quality of these images, but each strategy has its advantages and disadvantages, depending on the site of treatment. In Paper I, a method was proposed that combined the advantages of other frequently used methods to create an improved method for generating daily images with CT-like image quality. This can contribute towards the goal of online adaptive in the near future with reduced uncertainties.This thesis will provide a brief introduction and an in-depth chapter to elucidate the background, better understand the physics of proton therapy, the process of treatment planning, and the need for adaptive planning.
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| 5. |
- Mondal, Amit Kumar, et al.
(författare)
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Long-Range Spin-Selective Transport in Chiral Metal-Organic Crystals with Temperature-Activated Magnetization
- 2020
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Ingår i: ACS Nano. - : AMER CHEMICAL SOC. - 1936-0851 .- 1936-086X. ; 14:12, s. 16624-16633
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Tidskriftsartikel (refereegranskat)abstract
- Room-temperature, long-range (300 nm), chirality-induced spin-selective electron conduction is found in chiral metal-organic Cu(II) phenylalanine crystals, using magnetic conductive-probe atomic force microscopy. These crystals are found to be also weakly ferromagnetic and ferroelectric. Notably, the observed ferromagnetism is thermally activated, so that the crystals are antiferromagnetic at low temperatures and become ferromagnetic above similar to 50 K. Electron paramagnetic resonance measurements and density functional theory calculations suggest that these unusual magnetic properties result from indirect exchange interaction of the Cu(II) ions through the chiral lattice.
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| 6. |
- Sang, Yutao, et al.
(författare)
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Temperature Dependence of Charge and Spin Transfer in Azurin
- 2021
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Ingår i: The Journal of Physical Chemistry C. - : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 125:18, s. 9875-9883
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Tidskriftsartikel (refereegranskat)abstract
- The steady-state charge and spin transfer yields were measured for three different Ru-modified azurin derivatives in protein films on silver electrodes. While the charge-transfer yields exhibit weak temperature dependences, consistent with operation of a near activation-less mechanism, the spin selectivity of the electron transfer improves as temperature increases. This enhancement of spin selectivity with temperature is explained by a vibrationally induced spin exchange interaction between the Cu(II) and its chiral ligands. These results indicate that distinct mechanisms control charge and spin transfer within proteins. As with electron charge transfer, proteins deliver polarized electron spins with a yield that depends on the protein's structure. This finding suggests a new role for protein structure in biochemical redox processes.
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