Ability of two comestible formulations of hydroxypropylmethylcellulose to lower serum cholesterol concentrations

High molecular weight hydroxypropylmethylcellulose (HPMC) is a water-soluble cellulosic ether that has recently been shown to reduce serum cholesterol levels when administered as a diet Jell-O® formulation. For long term therapy, it would be desirable to formulate HPMC into a palatable, portable formulation. In this study, the ability of HPMC to lower cholesterol levels was compared between cookie and diet Jell-O® formulations. A randomized, double-blind cross-over placebo controlled study was conducted at the General Clinical Research Centre within the University of Michigan Medical Centre. Twelve healthy, mildly hypercholesterolemic individuals participated in the three one-week phases: HPMC in a cookie formulation, HPMC in a diet Jell-O® formulation and a placebo formulation. Dietary intake was reproduced exactly in each phase. Total cholesterol levels were reduced by 14 ± 8% (P < 0.05) after one week of administration of HPMC in the cookie formulation and 19 ± 7% (P < 0.05) using the diet Jell-O® formulation, compared to placebo. LDL cholesterol levels were reduced by 19 ± 13% (P < 0.05) and 26 ± 6% (P < 0.05), respectively. In vitro and canine experiments suggested that the tendency to smaller reductions in total and LDL cholesterol levels achieved with the cookie formulation were associated with the slower development of viscosity in solution. Notwithstanding the slightly less impressive clinical results, the cookie formulation offers a palatable, portable and effective alternative to the diet Jell-O® formulation of HPMC

DNMT3A haploinsufficiency transforms FLT3ITD myeloproliferative disease into a rapid, spontaneous, and fully penetrant acute myeloid leukemia

Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3ITD) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3afloxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency.FLT3ITD/DNMT3A-mutant primary human and murine AML exhibit a similar pattern of global DNA methylation associated with changes in the expression of nearby genes. In the murine model, rescuing Dnmt3a expression was accompanied by DNA remethylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Dissection of the cellular architecture of the AML model using single-cell assays, including single-cell RNA sequencing, identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci and responsive to DNMT3A levels. Thus, Dnmt3a haploinsufficiency transforms Flt3ITD myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation