Pyruvate Anaplerosis Is a Targetable Vulnerability in Persistent Leukaemic Stem Cells

Deregulated oxidative metabolism is a hallmark of leukaemia. While tyrosine kinase inhibitors (TKIs) such as imatinib have increased survival of chronic myeloid leukaemia (CML) patients, they fail to eradicate disease-initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays, we generate multi-omics datasets that offer unique insight into metabolic adaptation and nutrient fate in patient-derived CML LSCs. We demonstrate that LSCs have increased pyruvate anaplerosis, mediated by increased mitochondrial pyruvate carrier 1/2 (MPC1/2) levels and pyruvate carboxylase (PC) activity, in comparison to normal counterparts. While imatinib reverses BCR::ABL1-mediated LSC metabolic reprogramming, stable isotope-assisted metabolomics reveals that deregulated pyruvate anaplerosis is not affected by imatinib. Encouragingly, genetic ablation of pyruvate anaplerosis sensitises CML cells to imatinib. Finally, we demonstrate that MSDC-0160, a clinical orally-available MPC1/2 inhibitor, inhibits pyruvate anaplerosis and targets imatinib-resistant CML LSCs in robust pre-clinical CML models. Collectively these results highlight pyruvate anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient-derived samples

Combined effects of exogenous enzymes and probiotic on Nile tilapia (Oreochromis niloticus) growth, intestinal morphology and microbiome

A study was carried out to investigate the combined effect of exogenous enzymes and probiotic supplementation on tilapia growth, intestinal morphology and microbiome composition. Tilapia (34.56 ± 0.05 g) were fed one of four diets (35% protein, 5% lipid); one of which was a control and the remaining three diets were supplemented with either enzymes (containing phytase, protease and xylanase), probiotic (containing Bacillus subtilis, Bacillus licheniformis and Bacillus pumilus) or enz-pro (the combination of the enzymes and probiotic). Tilapia fed diet supplemented with enz-pro performed better (P < 0.05) than tilapia fed the control and probiotic supplemented diets in terms of final body weight (FBW), specific growth rate (SGR), feed conversion ratio (FCR) and protein efficiency ratio (PER). The dietary treatments did not affect somatic indices. The serum lysozyme activity was significantly higher (P < 0.05) in tilapia fed the probiotic supplemented diet than of those fed the remaining experimental diets. The intestinal perimeter ratio was higher (P < 0.05) in tilapia fed enz-pro supplemented diet when compared to those fed with the control and probiotic supplemented diets. Goblet cells abundance, microvilli diameter and total enterocyte absorptive surface was higher (P < 0.05) in tilapia fed diet supplemented with enz-pro than those fed the control diet. High-throughput sequencing revealed that majority of reads derived from the tilapia digesta belonged to members of Fusobacteria (predominantly Cetobacterium) distantly followed by Proteobacteria and Firmicutes. The alpha and beta diversities did not differ among dietary treatments indicating that the overall microbial community was not modified to a large extent by dietary treatment. In conclusion, supplementation of the diet with a combination of enzymes and probiotic is capable of improving tilapia growth and intestinal morphology without deleterious effect on the intestinal microbial composition

Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells

Abstract Deregulated oxidative metabolism is a hallmark of leukaemia. While tyrosine kinase inhibitors (TKIs) such as imatinib have increased survival of chronic myeloid leukaemia (CML) patients, they fail to eradicate disease-initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays, we generate multi-omics datasets that offer unique insight into metabolic adaptation and nutrient fate in patient-derived CML LSCs. We demonstrate that LSCs have increased pyruvate anaplerosis, mediated by increased mitochondrial pyruvate carrier 1/2 (MPC1/2) levels and pyruvate carboxylase (PC) activity, in comparison to normal counterparts. While imatinib reverses BCR::ABL1-mediated LSC metabolic reprogramming, stable isotope-assisted metabolomics reveals that deregulated pyruvate anaplerosis is not affected by imatinib. Encouragingly, genetic ablation of pyruvate anaplerosis sensitises CML cells to imatinib. Finally, we demonstrate that MSDC-0160, a clinical orally-available MPC1/2 inhibitor, inhibits pyruvate anaplerosis and targets imatinib-resistant CML LSCs in robust pre-clinical CML models. Collectively these results highlight pyruvate anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient-derived samples

Modelling the dynamics of bus use in a changing travel environment using panel data

Travel mode choice, Dynamics, Panel data, Unobserved heterogeneity, State dependence, Initial conditions,

Barrett\u27s esophagus: Histology and immunohistology

The following on histology and immunohistology of Barrett\u27s esophagus (BE) includes commentaries on the various difficulties remaining in reaching a consensus on the definition of BE; the difficulties in the characterization of intestinal and cardiac mucosa, and in the role of submucosal glands in the development of BE; the importance of a new monoclonal antibody to recognize esophageal intestinal mucosa; the importance of pseudo goblet cells; the best techniques for the endoscopic detection of Barrett\u27s epithelium; and the biomarkers for identification of patients predisposed to the development of BE. © 2011 New York Academy of Sciences

Digestibility and pricing of Chlorella sorokiniana meal for use in tilapia feeds

Several microalgae contain in excess of 50 % crude protein with amino acid profile comparable to that of fish meal. In addition, high polyunsaturated fatty acid contents encourage their use in animal feeding and nutrition, particularly in the formulation and processing of aquafeeds. This study aims at estimating the feasibility of Chlorella meal as feed ingredient for the feeding and nutrition of farmed tilapia based upon digestibility data. Juvenile tilapia were stocked in conical-bottomed tanks (200 L) with superficial, continuous water flow, and fed to apparent satiation in three daily meals with a reference diet and a test diet containing 30 % lyophilized Chlorella sorokiniana added of an inert marker. Feces were collected overnight by sedimentation in refrigerated, plastic containers coupled to the tanks and analyzed for determination of chemical composition and inert marker contents to estimate apparent digestibility coefficients (ADCs) of protein and energy of Chlorella meal; registered ADCs of Chlorella meal were 90.5 and 84.22, respectively. A pricing model considering the quantity of digestible nutrient was proposed based on ADCs of Chlorella and compared with the price of fishmeal (FM) and soybean meal (SBM). The indicative prices to elicit the use of Chlorella as a protein source rather than FM or SBM for the feed and nutrition of tilapia were 2.65 USD kg−1 and 0.66 USD kg−1, respectively