Modification of poly(lactate) via polymer blending with microbially produced poly[(R)-lactate-co-(R)-3-hydroxybutyrate] copolymers.

This study investigated the effect of polymer blending of microbially produced poly[(R)-lactate-co-(R)-3-hydroxybutyrate] copolymers (LAHB) with poly(lactate) (PLA) on their mechanical, thermal, and biodegradable properties. Blending of high lactate (LA) content and high molecular weight LAHB significantly improved the tensile elongation of PLA up to more than 250 % at optimal LAHB composition of 20-30 wt%. Temperature-modulated differential scanning calorimetry and dynamic mechanical analysis revealed that PLA and LAHB were immiscible but interacted with each other, as indicated by the mutual plasticization effect. Detailed morphological characterization using scanning probe microscopy, small-angle X-ray scattering, and solid-state NMR confirmed that PLA and LAHB formed a two-phase structure with a characteristic length scale as small as 20 nm. Because of mixing in this order, the polymer blends were optically transparent. The biological oxygen demand test of the polymer blends in seawater indicated an enhancement of PLA biodegradation during biodegradation of the polymer blends.

A covalent fragment-based strategy targeting a novel cysteine to inhibit activity of mutant EGFR kinase.

Several generations of ATP-competitive anti-cancer drugs that inhibit the activity of the intracellular kinase domain of the epidermal growth factor receptor (EGFR) have been developed over the past twenty years. The first-generation of drugs such as gefitinib bind reversibly and were followed by a second-generation such as dacomitinib that harbor an acrylamide moiety that forms a covalent bond with C797 in the ATP binding pocket. Resistance emerges through mutation of the T790 gatekeeper residue to methionine, which introduces steric hindrance to drug binding and increases the Km for ATP. A third generation of drugs, such as osimertinib were developed which were effective against T790M EGFR in which an acrylamide moiety forms a covalent bond with C797, although resistance has emerged by mutation to S797. A fragment-based screen to identify new starting points for an EGFR inhibitor serendipitously identified a fragment that reacted with C775, a previously unexploited residue in the ATP binding pocket for a covalent inhibitor to target. A number of acrylamide containing fragments were identified that selectively reacted with C775. One of these acrylamides was optimized to a highly selective inhibitor with sub-1 µM activity, that is active against T790M, C797S mutant EGFR independent of ATP concentration, providing a potential new strategy for pan-EGFR mutant inhibition.

Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor.

Histone acetylation is a post-translational modification of histones that is catalyzed by histone acetyltransferases (HATs) and plays an essential role in cellular processes. The HAT domain of EP300/CBP has recently emerged as a potential drug target for cancer therapy. Here, we describe the identification of the novel, highly potent, and selective EP300/CBP HAT inhibitor DS-9300. Our optimization efforts using a structure-based drug design approach based on the cocrystal structures of the EP300 HAT domain in complex with compounds 2 and 3 led to the identification of compounds possessing low-nanomolar EP300 HAT inhibitory potency and the ability to inhibit cellular acetylation of histone H3K27. Optimization of the pharmacokinetic properties in this series resulted in compounds with excellent oral systemic exposure, and once-daily oral administration of 16 (DS-9300) demonstrated potent antitumor effects in a castrated VCaP xenograft mouse model without significant body weight loss.

Discovery of EP300/CBP histone acetyltransferase inhibitors through scaffold hopping of 1,4-oxazepane ring.

EP300 and its paralog CBP play an important role in post-translational modification as histone acetyltransferases (HATs). EP300/CBP inhibition has been gaining attention as an anticancer treatment target in recent years. Herein, we describe the identification of a novel, highly selective EP300/CBP inhibitor, compound 11 (DS17701585), by scaffold hopping and structure-based optimization of a high-throughput screening hit 1. Compound 11 (DS17701585) shows dose-dependent inhibition of SRY-box transcription factor 2 (SOX2) mRNA expression in a human lung squamous cell carcinoma cell line LK2-xenografted mouse model.

4-Pyridone-3-carboxylic acid as a benzoic acid bioisostere: Design, synthesis, and evaluation of EP300/CBP histone acetyltransferase inhibitors.

Histone acetyltransferases (HATs) play a crucial role in post-translational modification. Among them, overexpression, mutation, or hyperfunction of EP300/CBP has been associated with various cancers. In this study, we identified the novel compound 2-chloro-5-[5-[(E)-[1-(3-chlorophenyl)-3-methyl-5-oxo-pyrazol-4-ylidene]methyl]-2-furyl]benzoic acid (1) as an EP300 HAT inhibitor via virtual screening. Further research has been focused on the design, synthesis, and in vitro biological evaluation of virtual hit derivatives. The studies revealed that 4-pyridone-3-carboxylic acid derivatives exhibited bioisosterism of benzoic acid. Replacement proved effective, providing compounds with similar EP300 HAT-inhibitory activity and improved cell growth-inhibitory activity compared to the benzoic acid analogs. Through these studies, we identified a potent and selective EP300/CBP HAT inhibitor.

Nanocelluloses and Related Materials Applicable in Thermal Management of Electronic Devices: A Review.

Owing to formidable advances in the electronics industry, efficient heat removal in electronic devices has been an urgent issue. For thermal management, electrically insulating materials that have higher thermal conductivities are desired. Recently, nanocelluloses (NCs) and related materials have been intensely studied because they possess outstanding properties and can be produced from renewable resources. This article gives an overview of NCs and related materials potentially applicable in thermal management. Thermal conduction in dielectric materials arises from phonons propagation. We discuss the behavior of phonons in NCs as well.

Improving thermal and mechanical properties of biomass-based polymers using structurally ordered polyesters from ricinoleic acid and 4-hydroxycinnamic acids.

Biomass-based copolymers with alternating ricinoleic acid and 4-hydroxycinnamic acid derivatives (p-coumaric acid, ferulic acid, and sinapinic acid) exhibit a repeating structure based on soft and hard segments, derived from ricinoleic and 4-hydroxycinnamic acids, respectively. To achieve this alternating sequence, copolymers were synthesised by the self-condensation of hetero-dimeric monomers derived by the pre-coupling of methyl ricinolate and 4-hydroxycinnamic acid. The glass transition temperature (T g) was observed to increase as the number of methoxy groups on the main chain increased; the T g values of poly(coumaric acid-alt-ricinoleic acid), poly(ferulic acid-alt-ricinoleic acid), and poly(sinapinic acid-alt-ricinoleic acid) are -15 °C, -4 °C, and 24 °C respectively, 58 °C, 69 °C, and 97 °C higher than that of poly(ricinoleic acid). The polymers were processed into highly flexible, visually transparent films. Among them, poly(sinapinic acid-alt-ricinoleic acid) bearing two methoxy groups on each cinnamoyl unit, is mechanically the strongest polymer, with an elastic modulus of 126.5 MPa and a tensile strength at break of 15.47 MPa.

The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models.

ROS1 gene rearrangement was observed in around 1-2 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. Crizotinib, an ALK/ROS1/MET inhibitor, is highly effective against ROS1-rearranged lung cancer and is used in clinic. However, crizotinib resistance is an emerging issue, and several resistance mechanisms, such as secondary kinase-domain mutations (e.g., ROS1-G2032R) have been identified in crizotinib-refractory patients. Here we characterize a new selective ROS1/NTRK inhibitor, DS-6051b, in preclinical models of ROS1- or NTRK-rearranged cancers. DS-6051b induces dramatic growth inhibition of both wild type and G2032R mutant ROS1-rearranged cancers or NTRK-rearranged cancers in vitro and in vivo. Here we report that DS-6051b is effective in treating ROS1- or NTRK-rearranged cancer in preclinical models, including crizotinib-resistant ROS1 positive cancer with secondary kinase domain mutations especially G2032R mutation which is highly resistant to crizotinib as well as lorlatinib and entrectinib, next generation ROS1 inhibitors.

Curing Effects on Interfacial Adhesion between Recycled Carbon Fiber and Epoxy Resin Heated by Microwave Irradiation.

The interfacial adhesion of recycled carbon fiber (CF) reinforced epoxy composite heated by microwave (MW) irradiation were investigated by changing the curing state of the epoxy resin. The recycled CF was recovered from the composite, which was prepared by vacuum-assisted resin transfer molding, by thermal degradation at 500 or 600 °C. Thermogravimetric analysis showed that the heating at 600 °C caused rough damage to the CF surface, whereas recycled CF recovered at 500 °C have few defects. The interfacial shear strength (IFSS) between recycled CF and epoxy resin was measured by a single-fiber fragmentation test. The test specimen was heated by MW after mixing the epoxy resin with a curing agent or pre-curing, in order to investigate the curing effects on the matrix resin. The IFSSs of the MW-irradiated samples were significantly varied by the curing state of the epoxy resin and the surface condition of recycled CF, resulting that they were 99.5 to 131.7% of oven heated samples Furthermore, rheological measurements showed that the viscosity and shrinking behaviors of epoxy resin were affected based on the curing state of epoxy resin before MW irradiation.

Targeting p300 Addiction in CBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation of MYC Expression.

UNLABELLED: Loss-of-function mutations in the CBP/CREBBP gene, which encodes a histone acetyltransferase (HAT), are present in a variety of human tumors, including lung, bladder, gastric, and hematopoietic cancers. Consequently, development of a molecular targeting method capable of specifically killing CBP-deficient cancer cells would greatly improve cancer therapy. Functional screening of synthetic-lethal genes in CBP-deficient cancers identified the CBP paralog p300/EP300 Ablation of p300 in CBP-knockout and CBP-deficient cancer cells induced G1-S cell-cycle arrest, followed by apoptosis. Genome-wide gene expression analysis revealed that MYC is a major factor responsible for the synthetic lethality. Indeed, p300 ablation in CBP-deficient cells caused downregulation of MYC expression via reduction of histone acetylation in its promoter, and this lethality was rescued by exogenous MYC expression. The p300-HAT inhibitor C646 specifically suppressed the growth of CBP-deficient lung and hematopoietic cancer cells in vitro and in vivo; thus p300 is a promising therapeutic target for treatment of CBP-deficient cancers. SIGNIFICANCE: Targeting synthetic-lethal partners of genes mutated in cancer holds great promise for treating patients without activating driver gene alterations. Here, we propose a "synthetic lethal-based therapeutic strategy" for CBP-deficient cancers by inhibition of the p300 HAT activity. Patients with CBP-deficient cancers could benefit from therapy using p300-HAT inhibitors.

Development of a C(60)-fullerene bonded open-tubular capillary using a photo/thermal active agent for liquid chromatographic separations by π-π interactions.

This short communication describes a newly developed open-tubular capillary which was coated with C60-fullerene by a covalent bonding via a photo/thermal active agent. We utilized perfluorophenyl azide (PFPA) as an active agent, which can be used for the "photo click" coupling of the carbon materials. The inner wall of a fused silica capillary was treated with silane conjugated PFPA, and then C60-fullerene was chemically modified by a photoreaction or a thermal reaction. Through evaluations of the capillaries by liquid chromatography, the separation characteristics of three polycyclic aromatic hydrocarbons (PAHs) were confirmed in both capillaries. With comparison of the retention behavior to a commonly used C18 column, the prepared capillaries showed the specific separation ability based on the π-π stacking by C60-fullerene. The capillary prepared by the thermal reaction provided the base line separation of phenanthrene, triphenylene, and benz[a]pyrene within 3min at 18.8cm capillary length.

Effective determination of a pharmaceutical, sulpiride, in river water by online SPE-LC-MS using a molecularly imprinted polymer as a preconcentration medium.

We report an effective and a quantitative analysis method for one of pharmaceuticals, sulpiride, in river water by online solid phase extraction (SPE) connected with liquid chromatography-mass spectrometry (LC-MS) using a molecularly imprinted polymer as a preconcentration medium. The polymer prepared with a pseudo template molecule showed the selective retention ability based on the interval recognition of functional groups in sulpiride. Also, the imprinted polymer provided an effective concentration of a trace level of sulpiride in offline SPE with dual washing processes using water and acetonitrile, although another imprinted polymer prepared by an authentic method using sulpiride and methacrylic acid as a template and a functional monomer, respectively, showed the selective adsorption only in organic solvents. Furthermore, we employed the imprinted polymer as the preconcentration column of online SPE-LC-MS and the results supposed that the proposed system allowed the quantitative analysis of sulpiride with high sensitivity and recovery (10ng/L at 96%). Additionally, the determination of sulpiride in real river water without an additional spiking was effectively achieved by the system.

A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1.

The occurrence of inactivating mutations in SWI/SNF chromatin-remodeling genes in common cancers has attracted a great deal of interest. However, mechanistic strategies to target tumor cells carrying such mutations are yet to be developed. This study proposes a synthetic-lethality therapy for treating cancers deficient in the SWI/SNF catalytic (ATPase) subunit, BRG1/SMARCA4. The strategy relies upon inhibition of BRM/SMARCA2, another catalytic SWI/SNF subunit with a BRG1-related activity. Immunohistochemical analysis of a cohort of non-small-cell lung carcinomas (NSCLC) indicated that 15.5% (16 of 103) of the cohort, corresponding to preferentially undifferentiated tumors, was deficient in BRG1 expression. All BRG1-deficient cases were negative for alterations in known therapeutic target genes, for example, EGFR and DDR2 gene mutations, ALK gene fusions, or FGFR1 gene amplifications. RNA interference (RNAi)-mediated silencing of BRM suppressed the growth of BRG1-deficient cancer cells relative to BRG1-proficient cancer cells, inducing senescence via activation of p21/CDKN1A. This growth suppression was reversed by transduction of wild-type but not ATPase-deficient BRG1. In support of these in vitro results, a conditional RNAi study conducted in vivo revealed that BRM depletion suppressed the growth of BRG1-deficient tumor xenografts. Our results offer a rationale to develop BRM-ATPase inhibitors as a strategy to treat BRG1/SMARCA4-deficient cancers, including NSCLCs that lack mutations in presently known therapeutic target genes.

Rapid separations by LC using ion-exchange media based on spongy monoliths.

Novel sponge-based monoliths containing ionic functional groups were developed for rapid separation and/or concentration of ionic solutes. The cationic and anionic spongy monoliths were prepared by chemical modifications of the pore surface on an original spongy monolith consisting of poly(ethylene-co-vinyl acetate). After hydrolysis of the spongy monolith, an anionic or a cationic moiety was introduced with succinyl chloride or acryloyl chloride/diethylamine, respectively. As a result of liquid chromatographic evaluations for the columns packed with these ionic spongy monoliths, both anionic and cationic monoliths showed ionic interactions with the opposing ionic solutes even if a higher flow rate (9.0 mL/min) was employed. Furthermore, we demonstrated the effective and rapid preconcentration of adenosine 5'-monophosphate in water using column-switching LC combined with the cationic spongy monolith as an online SPE adsorbent.

Hybridization of a macroporous sponge and spherical microporous adsorbents for high throughput separation of ionic solutes.

Hybrid materials using a macroporous sponge and spherical microporous adsorbents have been developed for an effective rapid pretreatment of water samples. Various adsorbents, including methacrylate series, divinylbenzene (DVB), and graphite particles, were utilized for hybridization with a macroporous sponge consisting of polyethylene and polyvinyl acetate, EVA resin. Both the EVA resin and each of the particles were thermally blended at 150°C with water-soluble pore templates, pentaerythritol and poly (oxyethylene, oxypropylene) triol. After molding as a columnar shape, the hybrid materials were observed by a scanning electron microscope both before and after washing with water/methanol sonication. Only methacrylate series could be effectively fixed onto the pore surface of sponge, whereas DVB and graphite particles were incorporated to the EVA matrix. We assume that the chemical interactions between EVA and adsorbents are very important for effective hybridization to fix the adsorbents onto the pore surface. Furthermore, we demonstrated the hybridization of ion-exchange resin and sponge for a high throughput purification of ionic compounds. The ion-exchangeable polymers prepared by methacrylic acid, 4-vinylpiridine, and p-styrene sulfonic acid with ethyleneglycol dimethacrylate could be fixed at a given ratio of "20, wt%", and its effective adsorption based on the ion-exchange ability was observed under rapid elution (3 mL min(-1)).

Antibacterial activities effectuated by co-continuous epoxy-based polymer materials.

We report antibacterial activities of the epoxy-resin-based monolithic media (epoxy monoliths) having macroporous co-continuous structure as well as hydrophobic and/or hydrophilic surface. Utilizing epoxy monoliths containing ammonium groups, the antibacterial experiments were examined using Escherichia coli. As the results, the monolithic media prepared with an epoxy monomer having nitrogen atoms clearly showed antibacterial activities, while those prepared using the monomer without nitrogen atom showed less antibacterial activities. Additionally, the quaternization of the epoxy polymers were expressed significant antibacterial activities. Further studies elucidated that the observed antibacterial activities involved the steep effect based on pH changing of solution and hydrophobic interactions by the quaternary ammonium.

Synthesis of novel polymer type sulfoxide solid phase combined with the porogen imprinting for enabling selective separation of polychlorinated biphenyls.

We developed a novel polymer type sulfoxide-modified solid phase enabling to achieve selective separation of polychlorinated biphenyls (PCBs) from insulation oil. In this study, firstly we prepared base-polymer based on the concept of the molecular imprinting to capture PCBs in selectively, then, the sulfoxide groups were modified on the pore surface of base-polymers by changing preparation methods. As results of liquid chromatographic analyses for the polymers as columns, the base-polymer prepared by xylene as a porogenic solvent showed selective retention ability for chlorinated aromatic compounds by the porogen imprinting effect. Additionally, the polymer-type sulfoxide solid phases showed highly retention ability for PCBs by increasing amount of introduced sulfoxide groups. Consequently, the results of separation of PCBs comparing to insulation oil suggested that the prepared solid phase can be used for the selective separation of PCBs at the same level as a commercially available media utilized for the regulated method.

Selective adsorption of water-soluble ionic compounds by an interval immobilization technique based on molecular imprinting.

Uniformity recognition sites for water-soluble ionic compounds were constructed onto the pores of porous polymer particles. This concept is based on a modified interval immobilization technique, which was used for the selective recognition of paralytic shellfish poison, saxitoxins (STXs). The results of batch adsorption and solid-phase extraction for one of the STX analogues, a prepared polymer that had special sites for the recognition of STXs, showed that the analogue could selectively recognize and concentrate STXs. Selective recognition was facilitated by interval-immobilized functional groups.

Inhibition of Hsp90 leads to cell cycle arrest and apoptosis in human malignant pleural mesothelioma.

INTRODUCTION: Heat shock protein 90 (Hsp90) is an abundant molecular chaperone that mediates the maturation and stability of a variety of proteins associated with the promotion of cell growth and survival. Inhibition of Hsp90 function leads to proteasomal degradation of its mis-folded client proteins. Recently, Hsp90 has emerged as being of prime importance to the growth and survival of cancer cells and its inhibitors have already been used in phase I and II clinical trials. METHODS: We investigated how 17-allylamino-17-demethoxygeldanamycin (17-AAG), a small molecule inhibitor of Hsp90, is implicated in human malignant pleural mesothelioma (MM). RESULTS: We found that 17-AAG led to significant G1 or G2/M cell cycle arrest, inhibition of cell proliferation, and decrease of AKT, AKT1, and survivin expression in all human malignant pleural mesothelioma cell lines examined. We also observed significant apoptosis induction in all MM cell lines treated with 17-AAG. Furthermore, 17-AAG induced apoptosis in freshly cultured primary MM cells and caused signaling changes identical to those in 17-AAG treated MM cell lines. CONCLUSION: These results suggest that Hsp90 is strongly associated with the growth and survival of MM and that inhibition of Hsp90 may have therapeutic potential in the treatment of MM.

Translational deregulation in PDK-1-/- embryonic stem cells.

PDK-1 is a protein kinase that is critical for the activation of many downstream protein kinases in the AGC superfamily, through phosphorylation of the activation loop site on these substrates. Cells lacking PDK-1 show decreased activity of these protein kinases, including protein kinase B (PKB) and p70S6K, whereas mTOR activity remains largely unaffected. Here we show, by assessing both association of cellular RNAs with polysomes and by metabolic labeling, that PDK-1-/- embryonic stem (ES) cells exhibit defects in mRNA translation. We identify which mRNAs are most dramatically translationally regulated in cells lacking PDK-1 expression by performing microarray analysis of total and polysomal RNA in these cells. In addition to the decreased translation of many RNAs, a smaller number of RNAs show increased association with polyribosomes in PDK-1-/- ES cells relative to PDK-1+/+ ES cells. We show that PKB activity is a critical downstream component of PDK-1 in mediating translation of cystatin C, RANKL, and Rab11a, whereas mTOR activity is less important for effective translation of these targets.