The BCR-ABL1 Inhibitors Imatinib and Ponatinib Decrease Plasma Cholesterol and Atherosclerosis, and Nilotinib and Ponatinib Activate Coagulation in a Translational Mouse Model

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Challenging behaviour among Indian children with visual impairment

The present study investigated the type and extent of challenging behaviour in three residential schools in India for children with visual impairment. Teachers completed a survey of challenging behaviour in one boys-only school (n = 123), one girls-only school (n = 88), and one co-educational school (n = 125). Among the 336 total children, 24% were identified as having challenging behaviours. The most frequently reported challenging behaviours were withdrawal (17%), hyperactivity (15%), stereotyped mannerisms (12%), irritability (12%), aggression (10%) and inappropriate speech (9%). Self-injury was rare (1%). The results highlight a need for effective school-based assessment and intervention strategies to address challenging behaviours among children with visual impairment

The BCR-ABL1 Inhibitors Imatinib and Ponatinib Decrease Plasma Cholesterol and Atherosclerosis, and Nilotinib and Ponatinib Activate Coagulation in a Translational Mouse Model

Treatment with the second and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) increases cardiovascular risk in chronic myeloid leukemia (CML) patients. We investigated the vascular adverse effects of three generations of TKIs in a translational model for atherosclerosis, the APOE*3Leiden.CETP mouse. Mice were treated for sixteen weeks with imatinib (150 mg/kg BID), nilotinib (10 and 30 mg/kg QD) or ponatinib (3 and 10 mg/kg QD), giving similar drug exposures as in CML-patients. Cardiovascular risk factors were analyzed longitudinally, and histopathological analysis of atherosclerosis and transcriptome analysis of the liver was performed. Imatinib and ponatinib decreased plasma cholesterol (imatinib, -69%, p p p p p = 0.002; ponatinib 10 mg/kg, -48%, p = 0.006), which were not affected by nilotinib. In addition, imatinib increased plaque stability. Gene expression and pathway analysis demonstrated that ponatinib enhanced the mRNA expression of coagulation factors of both the contact activation (intrinsic) and tissue factor (extrinsic) pathways. In line with this, ponatinib enhanced plasma levels of FVII, whereas nilotinib increased plasma FVIIa activity. While imatinib showed a beneficial cardiovascular risk profile, nilotinib and ponatinib increased the cardiovascular risk through induction of a pro-thrombotic state.KEYWORDS: animal model cardiovascular disease; atherosclerosis; cardiovascular side effects; cholesterol; chronic myeloid leukemia; coagulation/thrombosis; lipids and lipoprotein metabolismCardiolog