HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells

HDAC6 is overexpressed in ovarian cancer and is known to be correlated with tumorigenesis. Accordingly, ACY-241, a selective HDAC6 inhibitor, is currently under clinical trial and has been tested in combination with various drugs. HDAC8, another member of the HDAC family, has recently gained attention as a novel target for cancer therapy. Here, we evaluated the synergistic anticancer effects of PCI-34051 and ACY-241 in ovarian cancer. Among various ovarian cancer cells, PCI-34051 effectively suppresses cell proliferation in wild-type p53 ovarian cancer cells compared with mutant p53 ovarian cancer cells. In ovarian cancer cells harboring wild-type p53, PCI-34051 in combination with ACY-241 synergistically represses cell proliferation, enhances apoptosis, and suppresses cell migration. The expression of pro-apoptotic proteins is synergistically upregulated, whereas the expressions of anti-apoptotic proteins and metastasis-associated proteins are significantly downregulated in combination treatment. Furthermore, the level of acetyl-p53 at K381 is synergistically upregulated upon combination treatment. Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors.     

Endometrial Epithelial ARID1A Is Required for Uterine Immune Homeostasis during Early Pregnancy

A growing body of work suggests epigenetic dysregulation contributes to endometriosis pathophysiology and female infertility. The chromatin remodeling complex subunit AT-rich interaction domain 1A (ARID1A) must be properly expressed to maintain normal uterine function. Endometrial epithelial ARID1A is indispensable for pregnancy establishment in mice through regulation of endometrial gland function; however, ARID1A expression is decreased in infertile women with endometriosis. We hypothesized that ARID1A performs critical operations in the endometrial epithelium necessary for fertility besides maintaining gland function. To identify alterations in uterine gene expression resulting from loss of epithelial ARID1A, we performed RNA-sequencing analysis on pre-implantation uteri from Ltf^iCre/+Arid1a^f/f and control mice. Differential expression analysis identified 4181 differentially expressed genes enriched for immune-related ingenuity canonical pathways including agranulocyte adhesion and diapedesis and natural killer cell signaling. RT-qPCR confirmed an increase in pro-inflammatory cytokine and macrophage-related gene expression but a decrease in natural killer cell signaling. Immunostaining confirmed a uterus-specific increase in macrophage infiltration. Flow cytometry delineated an increase in inflammatory macrophages and a decrease in uterine dendritic cells in Ltf^iCre/+Arid1a^f/f uteri. These findings demonstrate a role for endometrial epithelial ARID1A in suppressing inflammation and maintaining uterine immune homeostasis, which are required for successful pregnancy and gynecological health.     

Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis

Non-alcoholic steatohepatitis (NASH) has pathological characteristics similar to those of alcoholic hepatitis, despite the absence of a drinking history. The greatest threat associated with NASH is its progression to cirrhosis and hepatocellular carcinoma. The pathophysiology of NASH is not fully understood to date. In this study, we investigated the pathophysiology of NASH from the perspective of glycolysis and the Warburg effect, with a particular focus on microRNA regulation in liver-specific macrophages, also known as Kupffer cells. We established NASH rat and mouse models and evaluated various parameters including the liver-to-body weight ratio, blood indexes, and histopathology. A quantitative phosphoproteomic analysis of the NASH rat model livers revealed the activation of glycolysis. Western blotting and immunohistochemistry results indicated that the expression of pyruvate kinase muscle 2 (PKM2), a rate-limiting enzyme of glycolysis, was upregulated in the liver tissues of both NASH models. Moreover, increases in PKM2 and p-PKM2 were observed in the early phase of NASH. These observations were partially induced by the downregulation of microRNA122-5p (miR-122-5p) and occurred particularly in the Kupffer cells. Our results suggest that the activation of glycolysis in Kupffer cells during NASH was partially induced by the upregulation of PKM2 via miR-122-5p suppression.     

Bias-error reduction in nanometer resolution microscopic motion tracking vision systems

Microscopic Motion Tracking Systems utilize sub-pixel algorithms to achieve close to nanometer precision motion measurement. This paper characterizes the bias-error of template matching image registration techniques which are commonly used to achieve this level of sub-pixel accuracy. An accurate functional expression for such bias error is derived, which shows how the error depends on image content. Furthermore, this expression is directly utilized in a bias reduction scheme that is shown to significantly reduce the bias error. The newly derived expressions and reduction schemes for bias are applied to a Microscopic Vision System that measures micro-object motion with close to nanometer resolution.     

pH-sensitive photocatalytic activities of TiO2/poly(vinyl alcohol)/poly(acrylic acid) composite hydrogels

The pH-sensitive photocatalytic system was prepared by embedding TiO₂ into poly(vinyl alcohol)/poly(acrylic acid) hydrogel. Two different type TiO₂/hydrogel composites, such as matrix and nanofiber, were prepared to investigate the morphological effects on the photocatalytic activity. TiO₂ was distributed uniformly in the composite hydrogel and kept the original anatase structure without any structural change. The photocatalytic activity of TiO₂ was evaluated based on the efficiency of photobleaching of dye. The photobleaching of dye was improved greatly as the pH was changed into basic condition and the larger surface area of hydrogel was available for TiO₂ by using nanofiber supports.     

Fabrication of Al matrix composite reinforced with submicrometer-sized Al<Subscript>2</Subscript>O<Subscript>3</Subscript> particles formed by combustion reaction between HEMM Al and V<Subscript>2</Subscript>O<Subscript>5</Subscript> composite particles during sintering

To fabricate an Al-V matrix composite reinforced with submicron-sized Al₂O₃ and Al_xV_y (Al₃V, Al₁₀V) phases, high energy mechanical milling (HEMM) and sintering were employed. By increasing the milling time, the size of mechanically milled powder was significantly reduced. In this study, the average powder size of 59 μm for Al, and 178 μm for V₂O₅ decreased with the formation of a new product, Al-Al₂O₃-Al_xV_y, with a size range from 1.3 μm to 2.6 μm formed by the in-situ combustion reaction during sintering of HEM milled Al and V₂O₅ composite powders. The in-situ reaction between Al and V₂O₅ during the HEMM and sintering transformed the Al₂O₃ and Al_xV_y (Al₃V, Al₁₀V) phases. Most of the reduced V reacted with excess the Al to form Al_xV_y (Al₃V, Al₁₀V) with very little V dissolved into Al matrix. By increasing the milling time and weight percentage of V₂O₅, the hardness of the Al-Al₂O₃-Al_xV_y composite sintered at 1173 K increased. The composite fabricated with the HEMM Al-20wt.%V₂O₅ composite powder and sintering at 1173 K for 2 h had the highest hardness.     

The pH effect for rare earth metals Nd, Pr and Y in aqueous solution dissolved Mg, Zn and Al

The pH variations of Mg, Zn and Al solutions to which had been added the rare earth metals Nd, Pr and Y were observed in 3.5 wt.% NaCl with respect to high energy mechanical ball milling effects. Mg was directly dissolved and exhibited a pH value of 10.5. On the other hand, Zn and Al needed to be saturated for a certain amount of time. The addition of rare earth metals played a role in increasing the pH with low reduction potentials. Additionally, mechanical ball milling provided high energy to Mg + x wt.% Zn + 0.5 wt.% Nd mixture by fracturing fragmentation of metals, which led to an increase in the pH when the mixture was immersed in 3.5 wt.% NaCl. The addition of Zn to Mg + 0.5 wt.% Nd caused a higher pH than when Mg + 0.5 wt.% Nd alone was added.     

Enhancement of the punch pin durability induced by the PVD coating in production process of the automotive inner pipe

This experimental studies were carried out in order to understand the effects of the PVD coating and the UNSM treatment of HSS55 (high speed steel 55) during the production of the automotive inner pipe by the plastic deformation of S45C. The field test and the SEM images revealed that the PVD coating is necessary in spite of the high compressive residual stresses which were formed at the head of a punch pin. Upon the application of the AlCrN coating with the UNSM treatment the productivity and reliability of a punch pin had improved more than about 2.6 times compared to that of the TiN coating without the UNSM treatment. It is likely that the improvement is caused by the decreased stress concentration factor by the ‘wrapped in oxides’ inside of an abrasion pit. The abrasion pits were mostly generated within range of 5% ∼ 50% of the diameter ratio from the end of a pin and reached the maximum value about 17% from the end of a pin.