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- Björn, Niclas, et al.
(författare)
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Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia
- 2020
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Ingår i: The Pharmacogenomics Journal. - : Nature Publishing Group. - 1470-269X .- 1473-1150. ; 20:2, s. 179-191
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Tidskriftsartikel (refereegranskat)abstract
- Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10−5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10−4), rs6118 in SERPINA5 (P-value = 5.83 × 10−4), and rs5877 in SERPINC1 (P-value = 1.07 × 10−3), and the genes CAPZA2 (P-value = 4.03 × 10−4) and SERPINC1 (P-value = 1.55 × 10−3). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10−4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10−8), and decrease (OR = 66.82, P-value = 5.92 × 10−9). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.
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| 2. |
- Björn, Niclas, et al.
(författare)
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The association of four genetic variants with myelosuppression in gemcitabine-treated Japanese is not evident in gemcitabine/carboplatin-treated Swedes
- 2022
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : John Wiley & Sons. - 1742-7835 .- 1742-7843. ; 130:4, s. 513-521
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Tidskriftsartikel (refereegranskat)abstract
- Gemcitabine/carboplatin-induced myelosuppressive adverse drug reactions (ADRs) are clinical problems leading to patient suffering and dose alterations. There is a need for personalised medicine to improve treatment effects and patients' well-being. We tested four genetic variants, rs11141915, rs1901440, rs12046844 and rs11719165, previously suggested as potential biomarkers for gemcitabine-induced leukopenia/neutropenia in Japanese patients, in 213 Swedish gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients. DNA was genotyped using TaqMan probes and real-time PCR. The relationships between the risk alleles and low toxicity (non-ADR: Common Terminology Criteria for Adverse Events [CTCAE] grades 0) or high toxicity (ADR: CTCAE grades 3-4) of platelets, leukocytes and neutrophils were evaluated using Fisher's exact test. The risk alleles did not correlate with myelosuppression, and the strongest borderline significance (not withstanding adjustment for multiple testing) was for rs1901440 (neutropenia, p = 0.043) and rs11719165 (leukopenia, p = 0.049) where the risk alleles trended towards lower toxicity, contrasting with previous study findings. Risk alleles and higher risk scores were more common among our patients. We conclude that the genetic variants do not apply to Swedish patients treated with gemcitabine/carboplatin. However, they can still be important in other populations and cohorts, especially in a gemcitabine monotherapy setting, where the causal genetic variation might influence myelosuppressive ADRs.
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| 3. |
- Björn, Niclas, 1990-, et al.
(författare)
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Whole-genome sequencing and gene network modules predict gemcitabine/carboplatin-induced myelosuppression in non-small cell lung cancer patients
- 2020
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Ingår i: npj Systems Biology and Applications. - : Nature Publishing Group. - 2056-7189. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Gemcitabine/carboplatin chemotherapy commonly induces myelosuppression, including neutropenia, leukopenia, and thrombocytopenia. Predicting patients at risk of these adverse drug reactions (ADRs) and adjusting treatments accordingly is a long-term goal of personalized medicine. This study used whole-genome sequencing (WGS) of blood samples from 96 gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients and gene network modules for predicting myelosuppression. Association of genetic variants in PLINK found 4594, 5019, and 5066 autosomal SNVs/INDELs with p ≤ 1 × 10−3 for neutropenia, leukopenia, and thrombocytopenia, respectively. Based on the SNVs/INDELs we identified the toxicity module, consisting of 215 unique overlapping genes inferred from MCODE-generated gene network modules of 350, 345, and 313 genes, respectively. These module genes showed enrichment for differentially expressed genes in rat bone marrow, human bone marrow, and human cell lines exposed to carboplatin and gemcitabine (p < 0.05). Then using 80% of the patients as training data, random LASSO reduced the number of SNVs/INDELs in the toxicity module into a feasible prediction model consisting of 62 SNVs/INDELs that accurately predict both the training and the test (remaining 20%) data with high (CTCAE 3–4) and low (CTCAE 0–1) maximal myelosuppressive toxicity completely, with the receiver-operating characteristic (ROC) area under the curve (AUC) of 100%. The present study shows how WGS, gene network modules, and random LASSO can be used to develop a feasible and tested model for predicting myelosuppressive toxicity. Although the proposed model predicts myelosuppression in this study, further evaluation in other studies is required to determine its reproducibility, usability, and clinical effect.
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| 6. |
- Brandén, Henrik, 1970-
(författare)
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Convergence Acceleration for Flow Problems
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Convergence acceleration techniques for the iterative solution of system of equations arising in the discretisations of compressible flow problems governed by the steady state Euler or Navier-Stokes equations is considered. The system of PDE is discretised using a finite difference or finite volume method yielding a large sparse system of equations. A solution is computed by integrating the corresponding time dependent problem in time until steady state is reached. A convergence acceleration technique based on semicirculant approximations is applied. For scalar model problems, it is proved that the preconditioned coefficient matrix has a bounded spectrum well separated from the origin. A very simple time marching scheme such as the forward Euler method can be used, and the time step is not limited by a CFL-type criterion. Instead, the time step can asymptotically be chosen as a constant, independent of the number of grid points and the Reynolds number. Numerical experiments show that grid and parameter independent convergence is achieved also in more complicated problem settings. A comparison with a multigrid method shows that the semicirculant convergence acceleration technique is more efficient in terms of arithmetic complexity. Another convergence acceleration technique based on fundamental solutions is proposed. An algorithm based on Fourier technique is provided for the fast application. Scalar model problems are considered and a theory, where the preconditioner is represented as an integral operator is derived. Theory and numerical experiments show that for first order partial differential equations, grid independent convergence is achieved.
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| 10. |
- Brandén, Henrik, et al.
(författare)
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Convergence acceleration for the steady state Euler equations
- 2000
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- We consider the iterative solution of systems of equations arising from discretizations of the non-linear Euler equations governing compressible flow. The differential equation is discretized on a structured grid, and the steady state solution is computed by a time-marching method.A convergence acceleration technique based on semicirculant approximations of the difference operator or the Jacobian is used. Implementation issues and variants of the scheme allowing for a reduction of the arithmetic complexity and memory requirement are discussed. The technique can be combined with a variety of iterative solvers, but we focus on non-linear explicit Runge-Kutta time-integration schemes. The results show that the single-stage forward Euler method can be used, and the time step is not limited by a CFL-criterion. Instead it can be chosen as a constant, independent of the number of grid points. This results in that the arithmetic work required for computing the solution is equivalent to the work required for a fixed number of residual evaluations.Two major advantages of the semicirculant convergence acceleration technique is that it contains few tunable parameters, and that it is robust with respect to the amount of artificial viscosity used in the discretization.
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