| 1. |
- Gregers, Jannie, et al.
(författare)
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Polymorphisms in the ABCB1 gene affect outcome and toxicity in Childhood Acute Lymphoblastic Leukemia
- 2012
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences pharmacokinetics in several anti-cancer drugs. We hypothesized that 1199G>A, 1236C>T, 2677G>A/T and 3435C>T variants of ABCB1 could affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL), since treatment includes known P-glycoprotein substrates and 3435C/T may affect methotrexate therapy. We studied 522 Danish children with ALL treated according to NOPHO ALL92 and ALL2000 protocols, 93% of all those eligible during 1992-2007. Risk of relapse was 2.9-fold increased for 41 patients with the 1199GA variant compared to 477 with 1199GG (p=0.001), and reduced by 61% and 40%, respectively for 421 patients with the 3435CT or 3435TT variants compared to 96 with 3435CC (overall p=0.02). Degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was higher in 71 patients with 3435TT variant (median nadirs: hemoglobin 3% and platelets 34/37% lower in3435CT/3435CC) compared to 160 patients with 3435CT/3435CC (Hemoglobin p=0.01 and platelets p<0.0001). We observed more liver toxicity after high-dose methotrexate in 109 patients with 3435CC variant versus 3435CT/TT (Median max alanineaminotransferase: 280 versus 142/111 U/L, p=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms and efficacy and toxicity in childhood ALL.
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| 2. |
- Gregers, Jannie, et al.
(författare)
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Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia
- 2012
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We hypothesized that polymorphisms in folate metabolism would affect treatment effects of the folate antagonist methotrexate (MTX). We studied whether ATIC347C>T, MTHFR677C>T, MTHFR1298C>A and SHMT1-1420C>T polymorphisms influence risk of disease or efficacy and toxicity of MTX in a large population of children with acute lymphoblastic leukaemia (ALL). The children were treated after standardized Nordic protocols with 5-8 g/m2 high-dose MTX courses and long term oral maintenance therapy with weekly MTX. Ninety-four percent (n=533) of the children diagnosed during a 16 year time period were included. The study showed that the polymorphisms had no effect on risk of ALL, MTX pharmacokinetics or outcome. However after high-dose MTX treatment, patients with MTHFR677TT/MTHFR677CT had more liver toxicity than patients with MTHFR677CC (alanine transferase: 174/154 versus 115U/L, p=0.049). Patients with MTHFR1298AA had more liver toxicity than patients with MTHFR1298CC (alanine transferase: 144 versus 108 U/L, p=0.04). More bone marrow toxicity was found in patients with MTHFR1298CC compared to MTHFR1298CT / MTHFR1298AA (Nadir means: Platelets 72 versus 109/93*109/L, p=0.0001). In conclusion this study supports that MTHFR1298C>A and MTHFR677C>T are associated with toxicity in MTX treatment and the MTHFR variants should be considered as markers for individualization of treatment in childhood ALL in combination with other pharmacogenetic markers.
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| 3. |
- Hedlund, Johanna, et al.
(författare)
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Cross-Border Climate Impacts in Food Trade Networks
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Climate impacts are predicted to become redistributed through countries’ reliance on food trade networks. This constitutes a significant challenge for climate adaptation planning, and may affect how countries engage in geopolitical and cooperative action. This paper explores potential impacts of climate change on global food trade networks. We ask: i) to what extent might climate change impacts entail a change in the structure of global food trade networks, and ii) how might a change in supply be distributed among the countries in trade blocs? We propose a simple network model to identify how climate change impacts on crops yields may be translated into changes in trade. Combining FAO and ISIMIP data, the model is applied to three key staple crops in the global food system: wheat, rice and maize. We use network community detection and functional cartography to analyse the degree to which global production is concentrated within different trade blocs before and after climate change impacts, and how countries distribute supply depending on their different network role. Our results predict that food trade networks may become more disaggregated as countries, particularly major global producers, may increasingly distribute their trade across modules with climate change impacts. Results also estimate that global food security may much depend on production change in a few major global producers, and whether trade blocs can balance production loss in some vulnerable countries. Overall, our model contributes a baseline scenario analysis of cross-border impacts on food trade networks, and insight into whether current food trade structures will allow counties to maintain current supply.
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