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- Cheung, LC, et al.
(författare)
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Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy
- 2023
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 37:1, s. 61-71
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Tidskriftsartikel (refereegranskat)abstract
- Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have a dismal prognosis. Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required. KMT2A-rearranged infant ALL cells are characterized by an abundance of promoter hypermethylation and exhibit high BCL-2 expression, highlighting potential for therapeutic targeting. Here, we show that hypomethylating agents exhibit in vitro additivity when combined with most conventional chemotherapeutic agents. However, in a subset of samples an antagonistic effect was seen between several agents. This was most evident when hypomethylating agents were combined with methotrexate, with upregulation of ATP-binding cassette transporters identified as a potential mechanism. Single agent treatment with azacitidine and decitabine significantly prolonged in vivo survival in KMT2A-rearranged infant ALL xenografts. Treatment of KMT2A-rearranged infant ALL cell lines with azacitidine and decitabine led to differential genome-wide DNA methylation, changes in gene expression and thermal proteome profiling revealed the target protein-binding landscape of these agents. The selective BCL-2 inhibitor, venetoclax, exhibited in vitro additivity in combination with hypomethylating or conventional chemotherapeutic agents. The addition of venetoclax to azacitidine resulted in a significant in vivo survival advantage indicating the therapeutic potential of this combination to improve outcome for infants with KMT2A-rearranged ALL.
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- Bergman, Lina, 1982, et al.
(författare)
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Cognitive impairment in preeclampsia complicated by eclampsia and pulmonary edema after delivery
- 2021
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Ingår i: Acta Obstetricia Et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 100:7, s. 1280-1287
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Tidskriftsartikel (refereegranskat)abstract
- Introduction We aimed to assess cognitive function in women with preeclampsia stratified by severity, before and after onset of disease. Material and methods Prospective study performed at a referral hospital in Cape Town, South Africa. Pregnant women between 20 and 42 weeks of gestation with eclampsia, pulmonary edema and preeclampsia without severe features, and a normotensive pregnancy were approached. Women were included at diagnosis of preeclampsia or at admission for delivery (women with normotensive pregnancies). Two cognitive assessments, the Cognitive Failure Questionnaire to assess the cognitive function subjectively before inclusion in the study, and Montreal Cognitive Assessment to assess the current cognitive function objectively before discharge from the hospital after delivery, were performed. Results We included 61 women with eclampsia, 28 with preeclampsia complicated by pulmonary edema, 38 with preeclampsia without severe features, and 26 with normotensive pregnancies. There was no difference in cognitive function from early pregnancy between groups. Women with eclampsia and preeclampsia complicated by pulmonary edema scored lower on the Montreal Cognitive Assessment at time of discharge compared with women with normotensive pregnancies. The results were attenuated in pulmonary edema after adjustment for confounders. Conclusions Women with preeclampsia complicated by pulmonary edema and in particular eclampsia had impaired cognitive function after onset of disease compared with women with normotensive pregnancies. The impairment did not seem to be present before onset of disease. Women with preeclampsia without severe features did not have impaired cognitive function.
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- Bergman, Lina, 1985, et al.
(författare)
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Multi-Fetal Pregnancy, Preeclampsia, and Long-Term Cardiovascular Disease
- 2020
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Ingår i: Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 0194-911X .- 1524-4563. ; 76:1, s. 167-175
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Tidskriftsartikel (refereegranskat)abstract
- This Swedish register-based cohort study determined the separate and joint contribution of preeclampsia and multi-fetal pregnancy on a woman's risk of cardiovascular disease (CVD) later in life. The study included 892 425 first deliveries between 1973 and 2010 of women born 1950 until 1971, identified in the Swedish Medical Birth Register. A composite outcome of CVD was retrieved through linkage with the National Patient and Cause of Death Registers. Cox proportional hazard regression was used to assess the risk of CVD in women who had preeclampsia in a singleton or multi-fetal pregnancy, adjusting for potential confounders, and presented as adjusted hazard ratios. Compared with women who had a singleton pregnancy without preeclampsia (the referent group), women with preeclampsia in a singleton pregnancy had an increased risk of CVD (adjusted hazard ratio 1.75 [95% CI, 1.64-1.86]). Women who had a multi-fetal pregnancy without or with preeclampsia did not have an increased risk of future CVD (adjusted hazard ratios 0.94 [95% CI, 0.79-1.10] and 1.25 [95% CI, 0.83-1.86], respectively). As opposed to preeclampsia in a first singleton pregnancy, preeclampsia in a first multi-fetal pregnancy was not associated with increased risk of future CVD. This may support the theory that preeclampsia in multi-fetal pregnancies more often occurs as a result of the larger pregnancy-related burden on the maternal cardiovascular system and excessive placenta-shed inflammatory factors, rather than the woman's underlying cardiovascular phenotype.
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