Search

Supplementary Figure S1. Identification of the p300 gene as a synthetic lethal hit. Supplementary Figure S2. Identification of MYC as a key factor in determining cancer cell survival under p300 depletion in CBP-KO cells or CBP depletion in p300-KO cells. Supplementary Figure S3. MYC transcriptional initiation is inactivated by suppression of histone H3K18/K27 acetylation upon p300 depletion in CBP-deficient cancer cells. Supplementary Figure S4. p300 depletion is lethal in cancer cells harboring loss-offunction mutations in CBP. Supplementary Figure S5. Response of CBP-deficient lung cancer cells to the p300 HAT inhibitor C646. Supplementary Figure S6. Depletion or inhibition of p300 suppresses growth of hematopoietic cancers with loss-of-function mutation of CBP. Supplementary Figure S7. Effect to BRD4 localization in the MYC locus in p300 depletion in CBP-deficient cancer cells. Supplementary Figure S8. CBP/CREBBP and p300/EP300 aberrations and known druggable aberrations of FGFR1 or ERBB2 amplification in lung squamous cell carcinomas and stomach adenocarcinomas. Supplementary Table S1. Raw data of survival fraction in siRNA screen. Supplementary Table S2. The top13 statistically significant pathways obtained from WikiPathways analysis. Supplementary Table S3. Genes commonly involved in the 13 functional pathways. Supplementary Table S4. CBP and p300 mutations in a variety of cancers. Supplementary Table S5. Gene status of tumor cell lines. Supplementary Table S6. siRNAs used in this study. Supplementary Table S7. Antibody for immunoblotting used in this study. Supplementary Table S8. TaqMan® Gene Expression Assays used in this study. Supplementary Table S9. Primer used in this study.

PDF files, 147K.

PDF file, 106K, Supplementary Table S1. BRG1-deficient and -proficient cell lines subjected to BRM knockdown Supplementary Table S2. Verification of gene alterations in cell lines subjected to BRM knockdown Supplementary Table S3. Analysis of missense BRG1 mutations using the Polyphen software Supplementary Table S4. Negative correlation between BRG1 deficiency and alterations in therapeutic target genes in 373 NSCLC cases from three studies (this study and Refs 32 and 33) Supplementary Table S5. Correlation between BRG1 deficiency and smoking in 369 NSCLC cases from three studies (this study and Ref 32 and 33).

PDF file, 1764K, Supplementary Figure S1. Immunohistochemical staining for BRG1 and BRM in cancer cell lines. Supplementary Figure S2. E431* and E608* Supplementary Figure S3. Fluorescence in situ hybridization for the detection of FGFR1 amplification in a case of squamous lung cell carcinoma. Supplementary Figure S4. Immunoblot analysis of SWI/SNF and ACF chromatinremodeling proteins. Supplementary Figure S5. Survival of H1299 (BRG1-deficient) and HeLa (BRG1-proficient) cells after shRNA-mediated knockdown of BRM (shBRM). Supplementary Figure S6. The effects of BRM knockdown on the morphologies of BRG1-deficient and proficient cancer cells. Supplementary Figure S7. Effect of BRM knockdown on the induction of senescence in BRG1-deficient and -proficient non-small-cell lung carcinoma cells.

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

The good dispersion and chemical modification of alumina (Al2O3) nanoparticles as filler were simultaneously performed by a wet–jet milling (WJM) process to disperse the nanoparticles effectively in the polymeric composite. The grafting densities of Al2O3 nanoparticles silane–coupling modified by WJM increased from 0.73 to 1.84 molecules/nm2 in hexyltriethoxysilane, and from 0.65 to 1.09 molecules/nm2 in 3–glycidoxypropyltriethoxysilane. Furthermore, the Al2O3 nanoparticles were dispersed to the primary particle size. In addition, the mechanical properties of the Al2O3/epoxy composite prepared by the in–situ mixing process were higher than those prepared by conventional dry mixing process. As results, the mechanical properties of the Al2O3/epoxy composite could be improved by optimizing the dispersion, chemical modification of the nanoparticles and mixing process of nanoparticles and polymer.

The dispersibility of hexagonal boron nitride (hBN) particles in epoxy resin with different chemical structures, such as bisphenol and naphthalene, was investigated. The viscosities of hBN slurries...

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 (Tg) was observed to increase as the number of methoxy groups on the main chain increased; the Tg 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.

To develop a highly thermally conductive composite film, two types of ceramic fillers with different shapes were bound with cellulose nanofiber (CNF) composite fibrils densely covered with nanodiamond (ND) particles. A hexagonal boron nitride (h-BN) filler with a plate-like structure was oriented in the in-plane direction of the CNF/ND nanosheets, increasing the in-plane thermal conductivity of the h-BN-based composite film by 38.7% from 4.45 to 6.17 W/m K compared with the raw CNF/ND composite film. Conversely, the Al2O3 particles inflected the CNF/ND nanosheets and lowered the orientation of the nanosheets. The in-plane thermal conductivity of the Al2O3-based composite film was lower than that of the CNF/ND film. To develop a highly thermally conductive CNF/ND/ceramic composite film, the ceramic filler should be oriented in the plane direction, and h-BN with a high thermal conductivity is a suitable filler.

A wet-rotating disc milling was used as a method to prepare ceramic slurry. The rheological measurements of the milled slurries showed that the apparent viscosity of the wet-rotating disc milled slurry was low and the slurry was nearly Newtonian behavior, whereas that of ball-milled slurry was more viscous and the slurry exhibited a very strong shear thinning effect. Furthermore, the internal structure composed of aggregated particles in the slurry of the ball-milled slurry was strong and fragile, whereas that of wet-rotating disc milled slurry was the soft structure due to good dispersion. Also, the relative densities of green compacts prepared by slip casting were measured by Archimedes’ method. The relative densities of green compact prepared by the wet-rotating disc milled slurries were higher than those of the ball-milled slurries, and were constant at around 65% without depending on the solids loading. The linear shrinkages of the sintered bodies prepared by ball-milled slurry increased from 14.2% to 21.2% with decreasing the solids loading of Al2O3 slurry. On the other hand, the linear shrinkages of sintered bodies prepared by wet-rotating disc milled slurries were constant at about 11%, resulting that the shrinkage of sintered body was suppressed by preparing well-dispersed and stable slurry with wet-rotating disc milling.

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.

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.

The in-plane thermal conductivity of cellulose nanofiber (CNF) composite film densely covered with nanodiamond (ND) particles has been improved by using the wet-rotating disc milling (WRDM) process and optimizing the compositional ratio of ND and CNF. The aspect ratio of CNF fibrils was increased by 42% using the WRDM. Furthermore, the in-plane thermal conductivities of CNF and ND/CNF films composed of WRDM-assisted CNF fibrils were improved with the increase of the aspect ratio of CNF fibrils. In addition, the mass ratio of ND to CNF and the in-plane thermal conductivity of the ND/CNF composite film were enhanced by using the WRDM-assisted ND suspensions owing to the improvement of dispersibility of ND particles. Consequently, the in-plane thermal conductivity of the ND/CNF film increased by 82% from 2.67 to 4.85 W/m K with the increase of the aspect ratio of CNF fibrils, thus improving the dispersibility of ND particles and optimizing the compositional ratio of ND and CNF. The dense adsorption of ND particles on the surface of CNF fibrils with high aspect ratio led to the improvement of the in-plane thermal conductivity of the composite film.

Thermally conductive and electrically insulating composite materials are required for thermal management in advanced electronic industry. The present work aimed at creating a composite film of cellulose nanofiber (CNF) and nanodiamond (ND) with superior thermal conductivity. The thermal conductivity of the prepared nanocomposite film was ∼2.7 Wm−1 K−1, which corresponds to triple of usual CNF/ND composites with similar composition. The distinct thermal conductivity is attributed to a unique nanostructure we made out in the nanocomposite film. The nanostructure can be characterized by CNF fibrils which are densely covered with ND particles.

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.

The exfoliation of layered muscovite with non-swelling property has been performed by combining various processes, such as heating, intercalation, and wet-jet milling. The c axis of muscovite was expanded from 2004.0 to 2022.8 pm at 800 °C without the destruction of crystallinity of muscovite. The heating at 800 °C led to the weak attraction force between potassium ions and silicate layers by hydroxylation of muscovite. The muscovite heated at 800 °C progressed the intercalation of dodecylammonium chloride (DDAC) into the layers effectively. Furthermore, the DDAC molecules were inserted to the interlayer of muscovite effectively by suppressing the formation of micelle of DDAC. The sedimentation test of wet-jet milled muscovite slurry showed that the relative packing density of muscovite was decreasing with increasing the amount of the intercalated DDAC. As results, the aspect ratio of muscovite prepared with combining the heating, the intercalation and the wet-jet milling was increased by 253% as compared to the raw muscovite. The aspect ratio was calculated from laser particle size distribution and thickness size distribution which was estimated from field emission-scanning electron microscopic images. The expansion of the interlayer led to the effective exfoliation of muscovite with high aspect ratio.

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., The treatment of ROS1-rearranged non-small cell lung cancer with the TKI crizotinib is limited due to the emergence of resistance. Here, the authors develop a new ROS1/NTRK inhibitor, DS-6051b, which overcomes crizotinib resistance in preclinical models.

The effects of microwave irradiation for resin-curing of carbon fiber/epoxy resin composite (CFRTS), which was fabricated by vacuum-assisted resin transfer molding (VARTM) method, were investigated at 2.45 GHz frequency. The mechanical properties of CFRTS cured by microwave irradiation for 20 min at 120 °C were similar as compared to the conventional oven for 300 min at 120 °C. Moreover, the CFRTS irradiated by microwave had better adherence property between fiber and resin as compared to conventional oven at same resin-curing time. From the relation between resin-curing and mechanical property, it was found that the curing rate of microwave-irradiated CFRTS was 15 times faster as compared to conventional heating. Furthermore, the activation energies for resin-curing reaction on conventional- and microwave-cured CFRTS were estimated to be 2.7 and 1.3 × 104 J/mol, respectively. The resin-curing reaction in CFRTS prepared by VARTM method was significantly promoted by microwave irradiation at short time.

Interfacial adhesion between carbon fiber (CF) and epoxy resin in carbon fiber-reinforced epoxy composite, which was prepared by different heating process such as semiconductor microwave (MW) device and conventional electric oven, has been evaluated quantitatively. The interfacial shear strength (IFSS) between CF and epoxy resin, which was an indicator of adhesion on the interface, was measured by a single fiber fragmentation test. The single fiber fragmentation test showed that the IFSSs of the prepared specimens were different by heating methods. In the case of MW process, the curing reaction of epoxy resin on the CF interface would be progressed preferentially due to the selective heating of CF, resulting that the IFSSs of specimens prepared by MW irradiation were increased by enhancing the output power of MW. However, the IFSSs of the specimens were decreased by excessively high output power because the matrix resin on the CF interface was thermally degraded. As results, by optimizing the MW c...

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.

The ability to exfoliate hexagonal boron nitride (h-BN) as laminated particles has been discussed by various mechanical high shear devices, such as vortex fluid (VF), planetary homogenizer(PH), ultrasonication (US) and wet-jet milling (WJM) with effective shear flow. The sedimentation test showed that the height of sediment of h-BN prepared by WJM was much higher than that of h-BN prepared by other mechanical methods, indicating that WJM process led to exfoliation of the laminated h-BN effectively. Also, the particle size distributions showed that the particle size of wet-jet milled h-BN was as similar as the initial particle size, whereas the particle sizes of h-BN prepared by other mechanical devices were less than 70% of the initial particle size. These results suggested that the difference of particle size after mechanical methods were based on the method of applying shearing force on the mechanical methods. In the mechanical methods such as VF, PH and US, the exfoliated h-BN would be destroyed even if the exfoliation of h-BN was progressed. On the other hand, in the case of the WJM, h-BN must be uniformly aligned in the thickness direction by pushing the slurry out at a high pressure, and the large impact energy is applied in the direction of the thickness of the h-BN particles. Therefore, it was found that the exfoliation of h-BN progressed by WJM was effective.

We report molecularly imprinted polymers (MIPs) for selective adsorption of proteins using a poly(ethylene glycol) (PEG)-based cross-linker with ionic monomers. To clarify the utility of the concept for preparation of the imprinted polymers using a PEG-based cross-linker, we employed lysozyme or cytochrome c as a template molecule. A few sulfonic functional monomers including sodium allylsulfonate, 2-acrylamido-2-methylpropanesulfonic acid, and sodium p-styrenesulfonate were utilized. After optimization of the concentration of the cross-linker and the washing process with a NaCl solution, we confirmed the complete eluting of the template lysozyme. The optimized lysozyme MIP showed the selective adsorption ability for lysozyme against the other proteins in higher salted condition, in which nonspecific ionic interaction due to the functional monomers were suppressed. Also, the imprinting factor toward the nonimprinted polymer was reached to over 8.6. Similar approaches were carried out for cytochrome c MIPs...

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. Cancer Res; 73(17); 5508–18. ©2013 AACR.

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.

To achieve selective adsorption of gaseous compounds, we synthesized the molecularly imprinted polymers (MIPs). In this study, we utilized two different types of MIPs, the first one was examination of the effect by the porogen imprinting, and another was authentic molecular imprinting by template and a functional monomer. The results of BET evaluation of MIPs showed that the specific surface area were depended on octanol–water partition coefficient (log Pow) between cross-linker and porogenic solvents, also became larger as log Pow of porogen being closer to that of cross-linker. Furthermore, the adsorption performance per unit weight of MIPs was observed under single gas adsorption by using MIPs prepared with target compound as porogenic solvents. As results, each MIP which was prepared with chloroform or toluene showed selective adsorption for each vapor in point of the adsorbed amount. Thus, MIPs tended to have selective adsorption ability for the used porogen in preparation. Additionally, the Gas-MIPs prepared with a functional monomer and template molecule adsorbed target compound in selectively as increase the amount of functional monomer and template molecule. Consequently, the authentic molecular imprinting method could be worked for the effective adsorption of gaseous compounds as well as the general procedures in solution.

We have developed hybrid photocatalysts by introducing molecular recognition sites to the surface of titanium dioxide (TiO2) nanoparticles. The synthesized hybrid photocatalysts indicated the selective recognition ability for target molecules based on specific molecular recognition sites constructed by the interval immobilization technique, and also the photostability of the recognition sites was confirmed by long time UV irradiation in an aqueous solution. Furthermore, the hybrid photocatalysts showed selective degradation performance to saxitoxins which are one of the famous neurotoxins. All basic and application results suggested that the newly developed methods for preparation of nano sized hybrid-TiO2 can be worked for selective adsorption and photodegradation of targeting compounds.

Background: RET gene rearrangement has been detected in several cancers including 1-2% and 50% of non-small cell lung cancer (NSCLC) and papillary thyroid carcinoma, respectively, and it is known as a driver mutation. Several US Food and Drug Administration (FDA)-approved multi-tyrosine kinase inhibitors (MTKIs) have shown inhibitory effects on RET kinase activity and have been tested in several clinical studies. However, MTKIs do not appear potent enough to show clinical benefits. The FDA-approved MTKIs have been reported to exhibit dose-limiting toxicity (DLT) at doses below those suppressing RET kinase activity. Kinase insert domain receptor (KDR) inhibition especially leads to anti-angiogenesis-related DLT such as hypertension. Thus, the development of highly potent and selective second-generation RET inhibitors is desired. DS-5010 is an orally available small-molecule RET inhibitor that shows a specific and highly potent activity against RET and gatekeeper-mutated RET (RET-GKm) and slight KDR activity. In this study, we characterized the in vitro and in vivo activities of DS-5010. Results: In biochemical assays of 106 kinases, RET and platelet-derived growth factor receptor (PDGFR) alpha/beta were inhibited more than 80% by 193 nM DS-5010. The half-maximal inhibitory concentration (IC50) values of DS-5010 against RET, RET-GKm (V804L) were single digit nano-molar even under a condition of high concentration of ATP; besides it against KDR was more than 1000 nM. In a Ba/F3-RET subcutaneous tumor model, DS-5010 dosing at 10 mg/kg twice daily (bid) induced tumor regression. Moreover, DS-5010 exhibited a similar antitumor effect in a Ba/F3-RET-GKm (V804L) subcutaneous tumor model. In contrast, the FDA-approved MTKIs (cabozantinib, vandetanib, and alectinib) showed no significant antitumor effect on a Ba/F3-RET-GKm (V804L) subcutaneous tumor model. In an LC2/ad NSCLC xenograft model, which has the RET-CCDC6 fusion gene, DS-5010 dosing at 1 mg/kg thrice daily (tid) induced tumor regression. To predict acquired mutations against FDA-approved MTKIs, resistant clones were established by prolonged incubation of Ba/F3-RET cells with cabozantinib. A sequence analysis revealed that all the resistant clones possessed V804E mutation in the RET kinase domain and DS-5010 inhibited cell proliferation of Ba/F3-RET (V804E) mutation in the low nano-molar range. However, the FDA-approved MTKIs failed to show strong growth inhibitory effects (half-maximal growth inhibition [GI50]: 1584-5381 nM). Conclusion: These results indicate that DS-5010 has potent in vitro and in vivo activities against RET and RET-GKm, suggesting the potential usefulness of the compound for targeted therapy of cancers with RET gene rearrangements and mutations. Moreover, its potential effectiveness against acquired MTKI-resistant cells was also demonstrated. We are currently performing investigational new drug-enabling studies of DS-5010. Citation Format: Yasuyuki Kaneta, Takahiro Komatsu, Masashi Miyamoto, Megumi Goto, Hidenori Namiki, Yoshihiro Shibata, Hideaki Kageji, Hiroaki Inagaki, Kiyoshi Nakayama, Yuichi Tominaga, Takeshi Isoyama. Preclinical characterization and antitumor efficacy of DS-5010, a highly potent and selective RET inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B173.

To achieve selective recognition of water-soluble ionic compounds, we developed an effective preparation method that can construct specific recognition sites on a cross-linked polymer surface using ionic complexes of functional monomers and template molecules. The specific ionic complexes used for selective recognition were attached on the surface of cross-linked polymer pores via a reaction between ionic complexes and unreacted vinyl groups on the polymer. In this paper, we show that ionic complexes can attach to the polymer surface by determining the number of unreacted vinyl groups on the cross-linked base polymer. The prepared polymers had greater effective adsorption ability than normally prepared molecularly imprinted polymer because there were no dead sites in the cross-linked network. Furthermore, according to chromatographic evaluations involving frontal analyses, the prepared polymer has selective recognition ability based on the interval recognition of ionic compounds. The adsorption isotherm also suggests selectivity for the template molecule on the prepared polymer. Finally, the paralytic shellfish poison saxitoxin was selectively extracted using the prepared polymer.

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.

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 -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. Citation Format: Hideaki Ogiwara, Mariko Sasaki, Takahiro Oike, Saito Higuchi, Yuichi Tominaga, Takashi Kohno. Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality by apoptotic cell death due to abrogation of MYC expression [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A29.

Affinity and kinetic analyses for the evaluation of lectin-reactive α -fetoprotein (AFP) were performed using a biosensor based on surface plasmon resonance (SPR). Human AFP, purified from HCC (hepatocellular carcinoma) patients, was immobilized on the surface of a sensor chip. The interaction of this bound AFP with three lectins, Lens culinaris agglutinin [LCA], concanavalin A [Con-A] and erythroagglutinating phytohemagglutinin [E-PHA]) were monitored in real-time with the change in the SPR response. These three lectins produced an increase in the SPR response, indicating that all three bound specifically to the immobilized AFP. The association ( k ass ) and the dissociation ( k diss ) rate constants clearly differed among the three lectin-AFP interactions. These affinity and kinetic analyses of the sugar binding specificities of lectins, employing a biosensor based on SPR, are expected to serve as a new technique with the potential for simple rapid evaluation of lectin-reactive AFP.

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 (10 ng/L at 96%). Additionally, the determination of sulpiride in real river water without an additional spiking was effectively achieved by the system.

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.