New Potent DOT1L Inhibitors for Evaluation in Mouse.

In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo.

[Bisalbuminemia: A case report].

Introduction: Bisalbuminemias consist in rare qualitative modifications of several aspects in the albumin pattern. Bisalbuminemias, most of which are not pathological, can be observed using capillary electrophoresis.

Case Reports: We report a case of hereditary bisalbuminemia diagnosed by chance while exploring chronic unexplained hypereosinophilia in a 42-year-old patient.

Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.

Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of , a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L.

Terlipressin in refractory shock induced by diltiazem poisoning.

Poisoning caused by calcium-channels blockers (CCB) can cause refractory vasoplegic shock, resulting in multiple-organ failure and death despite maximal therapy including high doses of vasopressors. We report one CCB-induced refractory shock complicated with lactate acidosis despite very high doses of epinephrine and norepinephrine. The hemodynamic status of the patient dramatically improved after intermittent boluses of terlipressin, which corrected the acidosis.