Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin−Sca-1+c-kit+CD48−CD150+) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence

Transcriptomic profiles of muscle, heart, and spleen in reaction to circadian heat stress in Ethiopian highland and lowland male chicken

Temperature stress impacts both welfare and productivity of livestock. Global warming is expected to increase the impact, especially in tropical areas. We investigated the biological mechanisms regulated by temperature stress due to the circadian temperature cycle in temperature adapted and non-adapted chicken under tropical conditions. We studied transcriptome profiles of heart, breast muscle, and spleen tissues of Ethiopian lowland chicken adapted to high circadian temperatures and non-adapted Ethiopian highland chicken under lowland conditions at three points during the day: morning, noon, and evening. Functional annotations and network analyses of genes differentially expressed among the time points of the day indicate major differences in the reactions of the tissues to increasing and decreasing temperatures, and also the two chickens lines differ. However, epigenetic changes of chromatin methylation and histone (de)acetylation seemed to be central regulatory mechanisms in all tissues in both chicken lines. Finally, all tissues showed differentially expressed genes between morning and evening times indicating biological mechanisms that need to change during the night to reach morning levels again the next day.</p

Effects of the Replacement of Soybean Meal with Pea as Dietary Protein Source on the Serum Protein Fractions of Broilers

ABSTRACT The aim of this study was to determine the effects of the replacement of different levels of protein derived from soybean meal with that from peas in broiler diets on serum protein fractions. A corn-soybean meal basal diet was formulated as the control diet (Control=C) (NRC, 1994), and then pea was added to the control diet to replace 20% (P20) or 40% (P40) of the crude protein of the control diet. The diets were randomly fed to 12 pens per treatment, each housing five birds, for 42 days. Blood samples were collected from 36 birds (3 birds x 4 pens x3 treatments) and the serum protein fractions were separated. Gamma-globulin percentage was higher in group P20 compared with C and P40 groups. Total protein, beta-globulin, and gamma-globulin concentrations were significantly higher in group P20 compared with those of both control and P40 group (p<0.05)