Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma.

PURPOSE: We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal treatment for high-risk neuroblastoma. EXPERIMENTAL DESIGN: The effects of the drug combination on cancer growth were examined in vitro and in animal models of MYCN-amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction. RESULTS: The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination. CONCLUSIONS: The combination of CBL0137 and panobinostat is effective and well-tolerated in preclinical models of aggressive high-risk neuroblastoma, warranting further preclinical and clinical investigation in other pediatric cancers. On the basis of its potential to boost IFN and immune responses in cancer models, the drug combination holds promising potential for addition to immunotherapies.

Multifunctional Two-Dimensional PtSe2-Layer Kirigami Conductors with 2000% Stretchability and Metallic-to-Semiconducting Tunability.

Two-dimensional transition-metal dichalcogenide (2D TMD) layers are highly attractive for emerging stretchable and foldable electronics owing to their extremely small thickness coupled with extraordinary electrical and optical properties. Although intrinsically large strain limits are projected in them (i.e., several times greater than silicon), integrating 2D TMDs in their pristine forms does not realize superior mechanical tolerance greatly demanded in high-end stretchable and foldable devices of unconventional form factors. In this article, we report a versatile and rational strategy to convert 2D TMDs of limited mechanical tolerance to tailored 3D structures with extremely large mechanical stretchability accompanying well-preserved electrical integrity and modulated transport properties. We employed a concept of strain engineering inspired by an ancient paper-cutting art, known as kirigami patterning, and developed 2D TMD-based kirigami electrical conductors. Specifically, we directly integrated 2D platinum diselenide (2D PtSe2) layers of controlled carrier transport characteristics on mechanically flexible polyimide (PI) substrates by taking advantage of their low synthesis temperature. The metallic 2D PtSe2/PI kirigami patterns of optimized dimensions exhibit an extremely large stretchability of ∼2000% without compromising their intrinsic electrical conductance. They also present strain-tunable and reversible photoresponsiveness when interfaced with semiconducting carbon nanotubes (CNTs), benefiting from the formation of 2D PtSe2/CNT Schottky junctions. Moreover, kirigami field-effect transistors (FETs) employing semiconducting 2D PtSe2 layers exhibit tunable gate responses coupled with mechanical stretching upon electrolyte gating. The exclusive role of the kirigami pattern parameters in the resulting mechanoelectrical responses was also verified by a finite-element modeling (FEM) simulation. These multifunctional 2D materials in unconventional yet tailored 3D forms are believed to offer vast opportunities for emerging electronics and optoelectronics.

Three dimensionally-ordered 2D MoS2 vertical layers integrated on flexible substrates with stretch-tunable functionality and improved sensing capability.

The intrinsically anisotropic crystallinity of two-dimensional (2D) transition metal dichalcogenide (2D TMD) layers enables a variety of intriguing material properties which strongly depend on the physical orientation of constituent 2D layers. For instance, 2D TMDs with vertically-aligned layers exhibit numerous dangling bonds on their 2D layer edge sites predominantly exposed on the surface, projecting significantly improved physical and/or chemical adsorption capability compared to their horizontally-oriented 2D layer counterparts. Such property advantages can be further promoted as far as the material can be integrated onto unconventional substrates of tailored geometry/functionality, offering vast opportunities for a wide range of applications which demand enhanced surface area/reactivity and mechanical flexibility. Herein, we report a new form of 2D TMDs, i.e., three-dimensionally ordered 2D molybdenum disulfide (2D MoS2) with vertically-aligned layers integrated on elastomeric substrates and explore their tunable multi-functionalities and technological promise. We grew large-scale (>2 cm2) vertically-aligned 2D MoS2 layers using a three-dimensionally patterned silicon dioxide (SiO2) template and directly transferred/integrated them onto flexible polydimethylsiloxane (PDMS) substrates by taking advantage of the distinguishable water-wettability of 2D MoS2vs. SiO2. The excellent structural integrity of the integrated vertical 2D MoS2 layers was confirmed by extensive spectroscopy/microscopy characterization. In addition, the stretch-driven unique tunability of their optical and surface properties was also examined. Moreover, we applied this material for flexible humidity sensing and identified significantly improved (>10 times) sensitivity over conventionally-designed horizontal 2D MoS2 layers, further confirming their high potential for unconventional flexible technologies.

Celastrus Orbiculatus Thunb. Reduces Lipid Accumulation by Promoting Reverse Cholesterol Transport in Hyperlipidemic Mice.

Previously, we found that Celastrus orbiculatus Thunb. (COT) decreases athero-susceptibility in lipoproteins and the aorta of guinea pigs fed a high-fat diet, and increases high-density lipoprotein (HDL). In the present study, we investigated the effect of COT in reducing lipid accumulation and promoting reverse cholesterol transport (RCT) in vivo and vitro. Healthy male mice were treated with high-fat diet alone, high-fat diet with COT (10.0 g/kg/d), or general fodder for 6 weeks. Serum levels of total cholesterol (TC), triglyceride (TG), HDL-C, non-HDL-C, and (3)H-cholesterol in plasma, liver, bile, and feces were determined. Pathological changes and the levels of TC and TG in liver were examined. The expression of hepatic genes and protein associated with RCT were analyzed. COT administration reduced lipid accumulation in the liver, ameliorated the pathological changes, and lessened liver injury, the levels of TG, TC, and non-HDL-C in plasma were decreased significantly, and COT led to a significant increase in plasma HDL-C and apolipoprotein A (apoA1). (3)H-cholesterol in plasma, liver, bile, and feces was also significantly increased in COT-treated mice compared to controls. Both mRNA and protein expression of SRB1, CYP7A1, LDLR, ATP-binding cassette transporters ABCA1, ABCG5, and LXRα were improved in COT-treated mice. An in vitro isotope tracing experiment showed that COT and its bioactive ingredients, such as celastrol, ursolic acid, oleanolic acid, and quercetin, significantly increased the efflux of (3)H-cholesterol. They also increased the expression of SRB1, ABCA1, and ABCG1 significantly in macrophages. Our findings provided a positive role of COT in reducing lipid accumulation by promoting RCT. These effects may be achieved by activating the SRB1 and ABC transporter pathway and promoting cholesterol metabolism via the CYP7A1 pathway in vivo. The effective ingredients in vitro are celastrol, ursolic acid, oleanolic acid, and quercetin.

Novel cathelicidin-derived antimicrobial peptides from Equus asinus.

In the present study, EA-CATH1 and EA-CATH2 were identified from a constructed lung cDNA library of donkey (Equus asinus) as members of cathelicidin-derived antimicrobial peptides, using a nested PCR-based cloning strategy. Composed of 25 and 26 residues, respectively, EA-CATH1 and EA-CATH2 are smaller than most other cathelicidins and have no sequence homology to other cathelicidins identified to date. Chemically synthesized EA-CATH1 exerted potent antimicrobial activity against most of the 32 strains of bacteria and fungi tested, especially the clinically isolated drug-resistant strains, and minimal inhibitory concentration values against Gram-positive bacteria were mostly in the range of 0.3-2.4 microg mL(-1). EA-CATH1 showed an extraordinary serum stability and no haemolytic activity against human erythrocytes in a dose up to 20 microg mL(-1). CD spectra showed that EA-CATH1 mainly adopts an alpha-helical conformation in a 50% trifluoroethanol/water solution, but a random coil in aqueous solution. Scanning electron microscope observations of Staphylococcus aureus (ATCC2592) treated with EA-CATH1 demonstrated that EA-CATH could cause rapid disruption of the bacterial membrane, and in turn lead to cell lysis. This might explain the much faster killing kinetics of EA-CATH1 than conventional antibiotics revealed by killing kinetics data. In the presence of CaCl(2), EA-CATH1 exerted haemagglutination activity, which might potentiate an inhibition against the bacterial polyprotein interaction with the host erythrocyte surface, thereby possibly restricting bacterial colonization and spread.