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Coactivator-associated arginine methyltransferase 1 (CARM1) is overexpressed in cancer, and it has emerged as an important target in acute myeloid leukemia and other hematologic malignancies. Janus kinase 2 (JAK2), that is activated by mutation in a variety of myeloid malignancies, can dictate chromatin structure via multiple effects. Here, we find that the hyperactivated JAK2-V617F mutant kinase phosphorylates CARM1, increasing its methyltransferase activity and altering its target specificity. Phospho-CARM1 binds and methylates the RUNX1 transcription factor, and the asymmetric dimethylation of R223 and R319 in RUNX1 is lost in engineered to express only non-phosphorylatable CARM1 mutant proteins in JAK2-V617F+ cell lines. The decreased CARM1 activity found in these cell lines impairs cell-cycle progression and induces apoptosis. We have established a link between activated JAK2 and CARM1 activity, and demonstrate that dual targeting of JAK2 and CARM1 is more effective than monotherapy in phospho-CARM1+ cell lines.

GeTe-based compounds are promising thermoelectric materials at medium temperature, while the performance of the GeTe matrix is at the mercy of its high hole concentration and high thermal conductiv...

Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks that are generally associated with transcriptional repression. However, we found that PRMT5 inhibition or depletion led to more genes being downregulated than upregulated, indicating that PRMT5 can also act as a transcriptional activator. Indeed, the global level of histone H3K27me3 increases in PRMT5 deficient cells. Although PRMT5 does not directly affect PRC2 enzymatic activity, methylation of histone H3 by PRMT5 abrogates its subsequent methylation by PRC2. Treating AML cells with an EZH2 inhibitor partially restored the expression of approximately 50% of the genes that are initially downregulated by PRMT5 inhibition, suggesting that the increased H3K27me3 could directly or indirectly contribute to the transcription repression of these genes. Indeed, ChIP-sequencing analysis confirmed an increase in the H3K27me3 level at the promoter region of a quarter of these genes in PRMT5-inhibited cells. Interestingly, the anti-proliferative effect of PRMT5 inhibition was also partially rescued by treatment with an EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects.

As an attractive lead-free thermoelectric candidate, GeTe-based materials have been intensively studied in recent years. However, the ZT value of pristine GeTe is limited around unit owing to the excessive hole concentration by intrinsic Ge vacancies. In this work, we report the synergistic enhancement of thermoelectric properties in rhombohedral GeTe by Bi–Zn codoping. It is found that Bi doping can effectively optimize the carrier concentration. Density functional calculations demonstrated that both Zn doping and the reduced c/a ratio by Bi doping could promote valence band convergence and Seebeck coefficient enhancement. Furthermore, lattice thermal conductivity is also significantly suppressed due to the Bi–Zn codoping introduced phonon scattering centers including point defects, Ge nano-precipitates, herringbone domains, twin boundaries, concentrated stress and density dislocations in the matrix. Consequently, a peak ZT of 2.0 at 700 K and a ZTave of 1.35 from 400 to 800 K are realized in Ge0.9Bi0.06Zn0.04Te.

Innate immune cells participate in the detection of tumor cells via complex signaling pathways mediated by pattern-recognition receptors, such as Toll-like receptors and nucleotide-binding and oligomerization domain–like receptors. These pathways are finely tuned via multiple mechanisms, including epigenetic regulation. It is well established that hematopoietic progenitors generate innate immune cells that can regulate cancer cell behavior, and the disruption of normal hematopoiesis in pathologic states may lead to altered immunity and the development of cancer. In this review, we discuss the epigenetic and transcriptional mechanisms that underlie the initiation and amplification of innate immune signaling in cancer. We also discuss new targeting possibilities for cancer control that exploit innate immune cells and signaling molecules, potentially heralding the next generation of immunotherapy.

Myelodysplastic syndromes (MDS) are hematopoietic stem and progenitor cell (HSPC) malignancies characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Epigenetic regulators are recurrently mutated in MDS, directly implicating epigenetic dysregulation in MDS pathogenesis. Here, we identified a tumor suppressor role of the acetyltransferase p300 in clinically relevant MDS models driven by mutations in the epigenetic regulators TET2, ASXL1, and SRSF2. The loss of p300 enhanced the proliferation and self-renewal capacity of Tet2-deficient HSPCs, resulting in an increased HSPC pool and leukemogenicity in primary and transplantation mouse models. Mechanistically, the loss of p300 in Tet2-deficient HSPCs altered enhancer accessibility and the expression of genes associated with differentiation, proliferation, and leukemia development. Particularly, p300 loss led to an increased expression of Myb, and the depletion of Myb attenuated the proliferation of HSPCs and improved the survival of leukemia-bearing mice. Additionally, we show that chemical inhibition of p300 acetyltransferase activity phenocopied Ep300 deletion in Tet2-deficient HSPCs, whereas activation of p300 activity with a small molecule impaired the self-renewal and leukemogenicity of Tet2-deficient cells. This suggests a potential therapeutic application of p300 activators in the treatment of MDS with TET2 inactivating mutations.

This study aimed to prepare a self-microemulsifying drug delivery system loaded with myricitrin (M-SMEDDS) to improve the low oral bioavailability of myricitrin. Prepared M-SMEDDS consisted of an oil phase (ethyl oleate), a surfactant (Cremophor EL35) and a co-surfactant (dimethyl carbinol). M-SMEDDS was characterized using the particle size, zeta potential and encapsulation efficiency, while the pharmacokinetics studies were also investigated. The prepared M-SMEDDS exhibited stable physicochemical properties with a small average droplet size (21.68 ± 0.15 nm), negative zeta potential (−23.17 ± 1.03 mV) and high encapsulation efficiency (92.73%). The in vitro release study showed that myricitrin was significantly released from M-SMEDDS compared with the free myricitrin. The relative oral bioavailability of M-SMEDDS was 2.47-fold higher than that of the free drug. These results indicated that the preparation, in vitro and in vivo studies of M-SMEDDS could obviously improve the solubility and oral bioavailability of myricitrin. This study therefore provides preliminary evidence for further clinical research and application of M-SMEDDS.

(Bi,Sb)2Te3 alloys have been widely used in thermoelectric cooling, but their poor mechanical properties limit the module size to reach higher cooling density. Here, we report the thermoelectric and mechanical properties of (Bi,Sb)2Te3–Ge0.5Mn0.5Te composites; Ge0.5Mn0.5Te has recently been reported to be a promising thermoelectric material with high hardness in a moderate temperature range. Alloying with Ge0.5Mn0.5Te not only reduces the lattice thermal conductivity, but also improves the mechanical properties. Along with carrier concentration regulation, both excellent thermoelectric and mechanical properties have been achieved in (Bi,Sb)2Te3–Ge0.5Mn0.5Te composites. The Vickers hardness increased from 0.45 Gpa for the pristine (Bi,Sb)2Te3 to 0.81 Gpa for the sample with 1.0% Ge0.5Mn0.5Te, and a Young's modulus of 37.06 Gpa was obtained for the one with 1% Ge0.5Mn0.5Te. By adjusting the carrier concentration, the final ZT value of (Bi,Sb)2Te3 > 1.1 at 350 K.

Na x CoO 2 was known 20 years ago as a unique example in which spin entropy dominates the thermoelectric behavior. Hitherto, however, little has been learned about how to manipulate the spin degree of freedom in thermoelectrics. Here, we report the enhanced thermoelectric performance of GeMnTe 2 by controlling the spin’s thermodynamic entropy. The anomalously large thermopower of GeMnTe 2 is demonstrated to originate from the disordering of spin orientation under finite temperature. Based on the careful analysis of Heisenberg model, it is indicated that the spin-system entropy can be tuned by modifying the hybridization between Te- p and Mn- d orbitals. As a consequent strategy, Se doping enlarges the thermopower effectively, while neither carrier concentration nor band gap is affected. The measurement of magnetic susceptibility provides a solid evidence for the inherent relationship between the spin’s thermodynamic entropy and thermopower. By further introducing Bi doing, the maximum ZT in Ge 0.94 Bi 0.06 MnTe 1.94 Se 0.06 reaches 1.4 at 840 K, which is 45% higher than the previous report of Bi-doped GeMnTe 2 . This work reveals the high thermoelectric performance of GeMnTe 2 and also provides an insightful understanding of the spin degree of freedom in thermoelectrics.