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BET inhibition has been shown to have a promising antitumor effect in multiple tumors. However, the impact of BET inhibition on antitumor immunity was still not well documented in HNSCC. In this study, we aim to assess the functional role of BET inhibition in antitumor immunity and clarify its mechanism. We show that BRD4 is highly expressed in HNSCC and inversely correlated with the infiltration of CD8sup+/supT cells. BET inhibition potentiates CD8sup+/supT cell-based antitumor immunity in vitro and in vivo. Mechanistically, BRD4 acts as a transcriptional suppressor and represses the expression of MHC class I molecules by recruiting G9a. Pharmacological inhibition or genetic depletion of BRD4 potently increases the expression of MHC class I molecules in the absence and presence of IFN-γ. Moreover, compared to PD-1 blocking antibody treatment or JQ1 treatment individually, the combination of BET inhibition with anti-PD-1 antibody treatment significantly enhances the antitumor response in HNSCC. Taken together, our data unveil a novel mechanism by which BET inhibition potentiates antitumor immunity via promoting the expression of MHC class I molecules and provides a rationale for the combination of ICBs with BET inhibitors for HNSCC treatment.

The Wnt/β-catenin signaling pathway plays extensive roles in cancer initiation, proliferation, and development, and has been implicated in the regulation of stem cells in the intestinal crypt, widely accepted as responsible for colorectal cancer (CRC) origination. This pathway has been a target of interest for many years for chemotherapeutic development of CRC due to its implication in most cases. Previously, a series of naphthoquinone analogs have been identified to inhibit the Wnt/β-catenin. It was postulated that these compounds exhibit their inhibitory activity via binding to β-catenin at the β-catenin/TCF4 interaction interface. In this study, we aimed to further define the critical pharmacophore for these compounds and verify their mechanisms of action for their abilities to inhibit the Wnt/β-catenin signaling pathway. Interestingly, our data suggested two of the compounds, compounds 3 and 6, may potently inhibit the Wnt/β-catenin signaling pathway via inhibition of the TCF4/DNA interaction, a novel finding compared to previous studies on these compounds. Our computational studies suggested that the compounds bound within the DNA binding HMG-box domain of TCF4 to elicit their inhibitory action. These compounds inhibited Wnt signaling in a dose dependent manner, suppressed Wnt direct target genes and demonstrated unforeseen degradation of the TCF4 protein. Thus, this study revealed a potentially novel mechanism of action of the chloro-naphthoquinone as possibly a multi-targeting scaffold, which warrants further investigation in future drug discovery on the 'undruggable" TCF proteins and an aberrantly activated Wnt/β-catenin signaling pathway.

Recent studies report that eutectic high entropy alloys (EHEA) which possess both high strength and high ductility have potential industrial applications. In the present work, the solidification behaviors and mechanical properties of directionally solidified AlCoCrFeNi2.1 EHEA obtained at different growth velocities are investigated. The microstructure of the as-cast AlCoCrFeNi2.1 EHEA is composed of bulky dendrites (NiAl phase) and lamellar eutectic structures which consists of the CoCrFeNi (FCC) phase and the NiAl (BCC) phase. Although the actual composition of the alloy is shown to slightly deviate from the eutectic point, it is interesting to observe that the full lamellar structure of this alloy is obtained through directional solidification. In order to explain this contradiction, the maximum interface temperature criterion and the interface response function ( IRF) theory are applied to calculate the velocity range of the transition from the primary phase to the eutectic, which is 1.2 μm/s-2×104 μm/s. Furthermore, the tensile test indicates that the directionally solidified AlCoCrFeNi2.1 EHEA possesses a good combination of strength (1340 Mpa) and ductility (30.5%) at 100μm/s, which can be attributed to the full lamellar eutectic structure after directional solidification. In addition, the compression tests demonstrated that the compressive strength of the axial specimen is greater than the radial specimen at the same growth velocity. Thus the directional solidification can effectively adjust the alignment of the eutectic structure and achieve better mechanical properties along the growth direction.

Three heat treatment processing routes (heat treatment at 1300 °C, 1350 °C and 1400 °C for 15min, 30min and 60min respectively, and following air cooling) were developed to investigate the dependence of mechanical properties on microstructure evolution in a new Ti-47.5Al–3Nb-3.5Cr (at.%) alloy. When the heat treatment temperature approaching the solution precipitation temperature of γ phase (Tγ-sol) (Tγ-sol

Recent studies have shown that the proportion of rice bulliform phytoliths with ≥9 fish-scale decorations can be used as a criterion to differentiate wild rice from its domesticated counterpart. The analysis of rice bulliform phytoliths recovered from 38 samples collected from eight archaeological sites dated to around 10,000–2200 BP suggests that the process of rice domestication in the Lower Yangtze River region lasted for around 6000 years and can be divided into three stages. Stage I was from around 10,000 to 6500 BP. The process of domestication was very slow, and even went backwards. Stage II was between 6500 and 5600 BP, when the process was accelerated. During stage III, from 4500 to 2200 BP, the domestication process eventually resulted in the breed of the modern rice.

An Fe/Al bilayer was prepared in this study using molecular beam epitaxy (MBE) at room temperature and the impact of annealing on the magnetic properties of the film was investigated together with the interfacial chemical state and heterostructures of the Fe/Al bilayer structures. The experimental results demonstrated that the Fe/Al bilayer material system exhibited an atomically sharp interface and was thermally stable to a temperature of 150 °C. To the best of our knowledge, preparing an atomically sharp metal-metal heterostructure of Fe/Al bilayer has yet to be reported and the thermal stability of the interface in the fabricated Fe/Al bilayer is of the utmost importance in fundamental studies and potential applications. Therefore, it is believed that the proposed deposition method can offer a general route for preparing atomical metal-metal interfaces and the reported results may in help further the development of the processing of Fe/Al magnetic memory devices.

Agricultural activities on the Qinghai–Tibetan Plateau (QTP) are difficult due to the hostile environment. Despite the difficulties, recently early agriculture has been documented by Holocene plant remains on the QTP. The details of the time, place, and mechanisms of agricultural origin as well as the evolution of agriculture on the QTP are still lacking. The Jiangxigou site (JXG2) contains artifacts dominated by microliths from the early to middle Holocene and provides important information on agricultural origins and evolution of prehistoric culture on the QTP. Here we report ancient starch grains and pollen extracted from ceramics and deposits excavated from each layer. The starch remains include 21 grains identical to starches from millets ( Setaria spp. and Panicum spp.), probably including 24% domesticated foxtail millet ( Setaria italica ), indicating that humans at 3000 m above sea level (masl) in the northeastern margin of the Qinghai–Tibetan Plateau (QTP) began to use millets ca. 5600 cal BP. Considering archeological evidence, the reasons for millet utilization by plateau residents may be associated with the expansion and influence of the Yangshao culture via the Loess Plateau.

Metformin has been suggested as an anti-cancer agent. However, increasing reports show that some tumors are resistant to metformin. Identification of factors affecting metformin mediated cancer therapy is of great significance. FGFR1 is a receptor-tyrosine-kinase that is frequently overexpressed in breast cancer, which is associated with poor-prognosis. To investigate the effect of FGFR1 overexpression on metformin-induced inhibition of breast cancer cells, we demonstrated that FGFR1 overexpression rendered MCF-7 and T47D cells resistant to metformin. In particular, we found that, in addition to AKT and ERK1/2 activation, FGFR1-induced activation of IRS1 and IGF1R, key regulators connecting metabolism and cancer, was associated with metformin resistance. Targeting IRS with IRS1 KO or IRS inhibitor NT157 significantly sensitized FGFR1 overexpressing cells to metformin. Combination of NT157 with metformin induced enhanced inhibition of p-IGF1R, p-ERK1/2 and p-mTOR. Moreover, we demonstrated that IRS1 functions as a critical mediator of the crosstalk between FGFR1 and IGF1R pathways, which involves a feedback loop between IRS1 and MAPK/ERK. Our study highlights the significance of FGFR1 status and IRS1 activation in metformin-resistance, which will facilitate the development of strategies targeting FGFR overexpression-associated metformin resistance.

C/EBP homologous protein (CHOP) is a multi-functional protein involved in the apoptosis pathway of endoplasmic reticulum stress (ERS) and is related to cancer progression. The purpose of this study was to assess CHOP expression as a prognostic biomarker in gastric cardia adenocarcinoma (GCA).The levels of CHOP mRNA and protein in GCA and matched adjacent non-cancerous tissues were evaluated by quantitative real-time-polymerase chain reaction (qRT-PCR) and western blot. Furthermore, the CHOP protein expression and localization were examined by immunohistochemistry in GCA and corresponding adjacent non-cancerous tissues, gastritis and normal cardiac tissues. The association of CHOP expression with clinical pathological parameters and prognosis of GCA patients was statistically analyzed.Compared with adjacent non-cancerous tissues, the CHOP was down-regulated at mRNA and protein levels in GCA (P0.01). In addition, immunohistochemistry analysis showed that CHOP positivity was lower in GCA than that in paired adjacent non-cancerous tissues, gastritis and normal tissues (P0.01). CHOP expression rate gradually decreased with an increase in clinical stage, tumor differentiation and lymph node metastasis of GCA (P0.05). Kaplan-Meier survival analysis revealed that low expression of CHOP correlated with poor prognosis of GCA patients. Moreover, univariate and multivariate analyses showed that CHOP was an independent prognostic marker for overall survival of GCA patients.Our results suggest that low CHOP expression predicts poor prognosis of GCA patients, and CHOP may be potentially a prognostic biomarker for GCA.

The evolution of the shear band, free volume, and structure in room temperature rolled Pd40Ni40P20 bulk metallic glass was investigated. It was found that the average shear band density increases monotonously with increasing strain. For the room temperature rolled Pd40Ni40P20 bulk metallic glass with a strain of 99%, a high density of shear bands with an average spacing of 31 nm was observed. The absolute free volume content was determined based on the free volume model and found to increase monotonously with increasing strain. The free volume content in the room temperature rolled Pd40Ni40P20 bulk metallic glass with a strain of 99% is 34% higher than its as-cast counterpart. Neither phase separation nor crystallization occurs in all the deformed samples. The coordination number of the first coordination shell decreases and the degree of disorder of atomic arrangement increases with increasing strain. (C) 2014 Elsevier B.V. All rights reserved.

Epitaxial Fe films are grown on Si(0 0 1) and Si(1 1 1) substrates by molecular beam epitaxy at room temperature. Several samples of one Fe/Si structure are subjected to rapid thermal annealing from 100 to 500 °C. The annealing impact on the morphological, magnetic properties and interfacial heterostructures of these samples is examined by atomic force microscopy, vibrating sample magnetometer and transmission electron microscopy, respectively. The results demonstrate that the material system Fe/Si grown at room temperature exhibits an abrupt interface and is thermally stable up to a temperature of 150 °C.

Starch grains from 31 modern samples of millets derived from the seeds of 7 species within the genus Setaria and 2 species within the genus Panicum were analyzed to determine diagnostic morphological characteristics. Ancient starch grains recovered from a sample of broomcorn millet (Panicum miliaceum) excavated from the Cishan site (10.0-7.6 cal yr BP) in the North China Plain were then subjected to the same analyses to determine the differences in morphologies, if any, between modern and ancient samples. The data indicate that morphological features, and particularly surface and fissure features, will allow for solid identifications of ancient millet starches, while size classes will be helpful, but will not be dependable taxonomic indicators. (C) 2011 Elsevier Ltd. All rights reserved.

Our studies investigating the existence of tumor-initiating cell (TIC) populations in human esophageal squamous cell carcinoma (ESCC) had identified a subpopulation of cells isolated from ESCC patient-derived tumor specimens marked by an ALDH