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- Skuladottir, AT, et al.
(author)
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A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome
- 2022
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 1598-
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Journal article (peer-reviewed)abstract
- Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10−24, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.
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- Gad, Helge, et al.
(author)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Journal article (peer-reviewed)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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- Skoglund, Karin, et al.
(author)
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In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients
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Other publication (other academic/artistic)abstract
- Introduction: The hepatic enzymes CYP3A4 and CYP3A5 metabolize the tyrosine kinase inhibitor imatinib into a large number of metabolites including the pharmacologically active N-desmethyl imatinib (CGP74588). Because the metabolic activity of CYP3A varies considerably between individuals and a previous pilot study suggested an inverse association between in vivo CYP3A metabolic activity and therapeutic outcome of imatinib, the primary aim of this study was to investigate the influence of CYP3A metabolic activity on the outcome of imatinib therapy in chronic myeloid leukemia patients.Methods: Fifty-five patients were included and CYP3A activity was estimated in vivo using quinine as a probe drug. Imatinib and CGP74588 trough concentrations in the plasma were determined at steady state in 34 patients. Cytogenetic and molecular responses after 12 months of first-line imatinib were retrospectively collected from patients’ medical records.Results: Patients with optimal response to imatinib (complete cytogenetic response (CCgR) or molecular response of BCR-ABL <1%) did not have different levels of CYP3A activity compared to non-optimal responders. Similar results were found when analyzing the molecular response and CCgR separately. Neither the imatinib trough concentration nor the CGP74588/imatinib ratio were significantly associated with CYP3A activity.Conclusion: CYP3A enzyme activity, as measured by quinine metabolic ratio, does not correlate with the plasma concentrations of imatinib or CGP74588 and is not predictive of imatinib therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the ratelimiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes such as plasma protein binding or transport protein activity to look for the major contributor to patient variability in imatinib plasma concentration.
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| 6. |
- Skoglund, Karin, et al.
(author)
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In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients
- 2016
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In: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 38:2, s. 230-238
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Journal article (peer-reviewed)abstract
- BACKGROUND: CYP3A metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in chronic myeloid leukemia (CML) patients. The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in CML patients.METHODS: Forty-three CML patients were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry.RESULTS: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to non-optimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P=0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity.CONCLUSIONS: CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.
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| 7. |
- Vikingsson, Svante, et al.
(author)
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Rapid Method to Measure Thioguanine Incorporation Into DNA
- 2011
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In: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 47:Supplement 1, s. S650-S650
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Journal article (other academic/artistic)abstract
- Background: The thiopurine drugs, 6-mercaptopurine, azathioprine, and thioguanine, are used in the treatment of acute lymphoblastic leukaemia (ALL). During treatment the thioguanine nucleotides formed are incorporated into the DNA, causing apoptosis due to the cells inability to repair the resulting damage. This mechanism is believed to be important for the effects of thiopurine drugs. We have developed a novel method for the determination of thioguanine incorporation into DNA which is both faster and cheaper than earlier methods.Monitoring the effects of thiopurine treatment by measuring thiopurine metabolites in erythrocytes has proven to be elusive due to the lack of good correlation between measured concentrations and thiopurine effects. If the incorporation is the main mechanism of thiopurine action, a reliable method capable of measuring the incorporation in an ordinary blood sample, such as the method we have developed, should provide a significantly better correlation with treatment effect.Material and Methods: Briefly, DNA extracted from buffy coat is degraded using nuclease P1 and alkaline phosphatase to produce free nucleosides which are purified by filtration. Thioguanosine and thymidine are separated and detected using an LC-MS/MS system and the ratio between the bases provides a measurement of the extent of thioguanine incorporation in DNA. The method has been successfully applied to cell culture samples as well as samples from patients treated orally with thiopurines.Results: In 8 inflammatory bowel disease patients treated with azathioprine the measured incorporation ranged from 2.2 to 8.4 thioguanine bases for every 10 000 thymidine bases (median 5.2). This is in agreement with earlier reports on incorporation in childhood leukemia patients.Conclusions: With the presented method it is possible to determine the incorporation of thioguanine into DNA during thiopurine treatment in a cost effective manner, but further research is needed to determine if there is a place for this type of methods in the monitoring of thiopurine treatment.An ongoing study aims to compare the incorporation to treatment effects as well as conventional measurements of erythrocyte metabolite levels. By this study we hope to determine if incorporation is a more reliable measurement to predict treatment effect and if the erythrocyte metabolite levels correlate with the incorporation.
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