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Summary MLL‐rearranged (MLL‐r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL‐r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI‐503, a potent menin‐MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI‐503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA‐seq following combined pharmacological inhibition of SD70 and MI‐503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI‐503 is a potential dual‐targeted therapy for MLL::AF9 AML. [ABSTRACT FROM AUTHOR]

BACKGROUND: Maltose is an essential derivative of starch. To understand the processability and stability of maltose‐containing foods, material characterization of the phase and state transition from its amorphous state is required. Although the crystallization of amorphous maltose is well understood, few studies have reported the relationship between the crystallization and the glass transition temperature (Tg)‐related molecular mobility. In this study, water sorption, crystallization, Tg‐related α‐relaxation, and the corresponding time factor for amorphous maltose and maltose / whey protein isolate (WPI) mixtures are measured at various water activity (aw) levels and 25 °C. RESULTS: The water‐additive principle for maltose / WPI mixtures was observed at aw ≤ 0.440 at the molecular level, whereas the crystallization of amorphous maltose occurred at high aw values (≥0.534). The crystal formation and crystallization kinetics of amorphous maltose were affected by water and WPI at aw ≥ 0.534 and 25 °C, as determined by X‐ray diffraction. The relationship between Tg and the water content was fitted by the Gordon–Taylor model, and its constant showed a compositional dependence for the maltose / WPI mixtures. The α‐relaxation temperature of the amorphous samples decreased due to water plasticization, but increased with an increase in the WPI quantity. The Strength (S) value for amorphous maltose, which was a quantitative estimate of the compositional effects on molecular mobility, was based on the William–Landel–Ferry (WLF) equation. CONCLUSION: The S concept exhibits considerable potential for application in controlling the crystallization of amorphous maltose and improving the processability and stability of maltose‐containing foods. © 2020 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Theoretical models suggest monetary policy is transmitted to commodity prices. We quantify this channel using several empirical methods under daily data. In early 2009, the US real interest rate became negative, with sample mean varying from 1.75 % (in the mid-1997 to January 28, 2009, subsample) to $$-1.50\,\%$$ (in January 29, 2009, to mid-September 2013 subsample). Gold displays higher risk-adjusted returns earlier, while copper and oil have higher risk-adjusted returns more recently. Shocks to the exchange rate and the real interest rate in VARs explain almost 30 % for oil and 32 % for copper more recently when impulse responses are more significant. The time-varying correlation of oil with the real interest rate in the more recent period is $$-0.462$$ , and its correlation with the exchange rate is $$-0.460$$ , compared to $$-0.089$$ and $$-0.120$$ , respectively, in the earlier period. Vine copula methods identify a dependence pattern of C-vine copula with t-copula in almost every pair among commodity prices, the real value of the US dollar and the US real interest rate. [ABSTRACT FROM AUTHOR]

Leukemia stem cells (LSC) are a rare population capable of limitless self-renewal and are responsible for the initiation, maintenance, and relapse of leukemia. Elucidation of the mechanisms underlying the regulation of LSC function could provide novel treatment strategies. Here, we show that TWIST1 is extremely highly expressed in the LSC of MLL-AF9+ acute myeloid leukemia (AML), and its upregulation is positively regulated by KDM4C in a H3K9me3 demethylation-dependent manner. We further demonstrate that TWIST1 is essential for the viability, dormancy, and self-renewal capacities of LSC, and that it promotes the initiation and maintenance of MLL-AF9-mediated AML. In addition, TWIST1 directly interacts and collaborates with HOXA9 in inducing AML in mice. Mechanistically, TWIST1 exerts its oncogenic function by activating the WNT5a/RAC1 axis. Collectively, our study uncovers a critical role of TWIST1 in LSC function and provides new mechanistic insights into the pathogenesis of MLL-AF9+ AML.

The dopaminergic neuron degeneration and loss that occurs in Parkinson's disease (PD) has been tightly linked to mitochondrial dysfunction. Although the aged-related cause of the mitochondrial defect observed in PD patients remains unclear, nuclear genes are of potential importance to mitochondrial function. Human peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α) is a multi-functional transcription factor that tightly regulates mitochondrial biogenesis and oxidative capacity. The goal of the present study was to explore the potential pathogenic effects of interference by the PGC-1α gene on N-methyl-4-phenylpyridinium ion (MPP + )-induced SH-SY5Y cells. We utilized RNA interference (RNAi) technology to probe the pathogenic consequences of inhibiting PGC-1α in the SH-SY5Y cell line. Remarkably, a reduction in PGC-1α resulted in the reduction of mitochondrial membrane potential, intracellular ATP content and intracellular H 2 O 2 generation, leading to the translocation of cytochrome c (cyt c) to the cytoplasm in the MPP + -induced PD cell model. The expression of related proteins in the signaling pathway (e.g., estrogen-related receptor α (ERRα), nuclear respiratory factor 1 (NRF-1), NRF-2 and Peroxisome proliferator-activated receptor γ (PPARγ)) also decreased. Our finding indicates that small interfering RNA (siRNA) interference targeting the PGC-1α gene could inhibit the function of mitochondria in several capacities and that the PGC-1α gene may modulate mitochondrial function by regulating the expression of ERRα, NRF-1, NRF-2 and PPARγ. Thus, PGC-1α can be considered a potential therapeutic target for PD.