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Deficiency in DNA repair proteins confers susceptibility to DNA damage, making cancer cells vulnerable to various cancer chemotherapies. 5‐Fluorouracil (5‐FU) is an anticancer nucleoside analog that both inhibits thymidylate synthase (TS) and causes DNA damage via the misincorporation of FdUTP and dUTP into DNA under the conditions of dTTP depletion. However, the role of the DNA damage response to its antitumor activity is still unclear. To determine which DNA repair pathway contributes to DNA damage caused by 5‐FU and uracil misincorporation, we examined cancer cells treated with 2ʹ‐deoxy‐5‐fluorouridine (FdUrd) in the presence of TAS‐114, a highly potent inhibitor of dUTPase that restricts aberrant base misincorporation. Addition of TAS‐114 increased FdUTP and dUTP levels in HeLa cells and facilitated 5‐FU and uracil misincorporation into DNA, but did not alter TS inhibition or 5‐FU incorporation into RNA. TAS‐114 showed synergistic potentiation of FdUrd cytotoxicity and caused aberrant base misincorporation, leading to DNA damage and induced cell death even after short‐term exposure to FdUrd. Base excision repair (BER) and homologous recombination (HR) were found to be involved in the DNA repair of 5‐FU and uracil misincorporation caused by dUTPase inhibition in genetically modified chicken DT40 cell lines and siRNA‐treated HeLa cells. These results suggested that BER and HR are major pathways that protect cells from the antitumor effects of massive incorporation of 5‐FU and uracil. Further, dUTPase inhibition has the potential to maximize the antitumor activity of fluoropyrimidines in cancers that are defective in BER or HR., In this study, we examined the protective role of DNA repair pathways on 5‐FU and uracil misincorporation into DNA by using several preclinical models. They revealed that the BER and HR pathways were responsible for preventing cytotoxic activity induced by 5‐FU and uracil misincorporation. This insight provides novel opportunity for certain types of DNA‐repair‐defective cancer to be treated by 5‐FU and dUTPase inhibitor, which dramatically enhances 5‐FU and uracil misincorporation.

Combination tablets containing multiple active pharmaceutical ingredients (APIs) are expected to improve patient convenience by decreasing the number of tablets to be taken; thus, numerous formulations containing multiple APIs have recently been developed. To allow for dose adjustments based on patient conditions, many tablets have a bisection line to allow equal division of tablets. However, there have been no investigations regarding content uniformity among divided combination tablets. Therefore, in this study, the content uniformity of combination tablets after division was investigated using near IR and low-frequency (LF) Raman spectroscopy imaging as well as the Japanese Pharmacopoeia (JP) content uniformity tests. As model drugs, five tablets of three combination drugs containing 3-(3,4-dihydroxyphenyl)-L-alanine (L-DOPA) and benserazide hydrochloride (BNS) as APIs for treating Parkinson's disease were bisected; the resultant 10 samples were subjected to the JP content uniformity tests. We found that acceptance values of L-DOPA and BNS were 11.0-21.9% and 13.3-17.5%, respectively, with some non-conformity to the maximum allowed acceptance value (15.0%) as per the current JP. Image analyses by near IR showed that L-DOPA, BNS, lactose, and corn starch were uniformly distributed in each tablet; moreover, LF Raman spectroscopy imaging also supported the result that L-DOPA, BNS, and lactose were evenly distributed. Therefore, drug content in the tablets was uniform; thus, careful manipulation was recommended in the tablet bisection. However, the results of bisection line specifications and hardness tests revealed that the ease of division differed depending on the tablets, which warrants attention.

In this paper, in order to propose an interface that reproduces a thermal sensation, the skin temperature change when a human touches an object was measured, and temperature reproduction was performed using a Peltier device. The response and followability of the Peltier device were evaluated in experiments using objects with different thermal properties. The results showed that the heat transfer was generally terminated when the object is touched for about 10 seconds, and after that the temperature change was small. Furthermore, using the manufactured thermal sensation presentation device, we attempted to generate the wet sensation of a plurality of dry fabrics. The subjects evaluated the wet sensation of the initial temperature controlled the fabrics (dry or having a moisture content of 20-30%). As a result we concluded that the wet sensation can be generated when the initial temperature of the dry fabrics is lower than the skin temperature.

We investigated the water contents in commercial semi-solid preparations used for pressure ulcer (PU) treatment using near-IR spectroscopy (NIRS) and compared the results with those measured using the Karl Fischer (KF) method. The aim of this study was to determine a standard method and select the appropriate topical preparation with the optimal moisture for PU treatment. The water absorption properties of bases and formulations were evaluated with a time-dependent factor using Transwell as the model membrane. KF and NIRS were applicable as measurement methods of the water content in semi-solid formulations. NIRS was shown to be a useful, simple, nondestructive tool that is more advantageous than the KF method. The water absorption characteristics tested using Transwell revealed that the rate of and capacity for water absorption are determined not only by the absorption ability of the polymer base but also by other factors, such as the osmotic pressure exerted by additives. KF and NIR measurements can be used to choose external skin preparations to control the amount of water in PU treatment.

Disaster risks are always unpredictable, and it is impossible to prepare with predefined functions of the systems including not only automatic mechanical systems but also human groups of engineers and administrators. In this paper, to tackle the problem of disaster risks reduction, we propose a practical design and demonstration of the mechanism of collaboration between humans and agents of network management systems. As an example function of the collaboration, we develop the collaborative agents mediating the human users and the agents dealing with the network management functions. From the evaluation experiments using prototypical implementations show the possibility of the actual effectiveness of the proposed mechanism.

Networking is an indispensable tool for disaster situations. Since it is predictable that there are no professional technicians around the place where the faults occur, a solution of collaborative problem solving between humans and agents makes the non-professionals to improve that situation. In this paper, to address the errors of the network under the disaster situation, we propose a multi-modal interaction mechanism for temporally organized groups of humans and agents who accidentally present at a short distance. A prototypical system including the proposed mechanism and the network management support agents shows that the flexible collaboration realizes the useful restoration.

Collaboration between humans and agents is an attractive solution for some severe works such as disaster response. Although many organizations are introducing chat-based interfaces for the conversation with the systems, it assumes a fixed relationship between the customers and the agents. In this study, we propose a support mechanism for the collaboration between humans and agents in the scenario of recovery from the fault in the network and system using autonomic network management systems based on the software agent framework. Through the experiments of collaboration in the tasks, we acquired some requirements to provide the effective support to them.

Background: Ribonucleotide reductase (RNR) is an essential metabolic enzyme that catalyzes a rate-limiting step for de novo dNTP biosynthesis via converting ribonucleotides to deoxyribonucleotides. dNTPs are also supplied through nucleoside salvage pathway in which dNTP is synthesized from extracellular nucleoside. The salvage pathway is also utilized for conversion of several nucleoside analogues to their active metabolites. Given the previous report showing that the inhibition of de novo pathway activates salvage pathway at least in vitro, RNR is considered as a promising target for combination therapy with nucleoside analogues. However, in vivo efficacy of selective RNR inhibitor in combination with nucleoside analogues has not been clarified yet. Previously, we reported a novel class of RNR inhibitor TAS1553, which is a selective and orally available small molecule abrogating protein-protein interaction between RNR subunits. Here, we evaluated the synergistic activity of TAS1553 and several nucleoside analogues in vitro as well as in vivo studies. Material and methods: Antiproliferative activity was assessed by CellTiter-Glo® 2.0 assay. Intracellular and intratumoral ara-CTP amounts were measured by HPLC analysis. Antitumor efficacy was evaluated in athymic nude mice bearing MV-4-11 (human AML) and CFPAC-1 (human pancreatic cancer) cell line. Results: To examine whether TAS1553 plus nucleoside analogues combination shows synergistic efficacy, we evaluated antiproliferative activity of TAS1553 in combination with some nucleoside analogues (cytarabine, gemcitabine, decitabine, and 2F-ara-A) to calculate the combination index (CI). TAS1553 exhibited synergistic antiproliferative activity (CI < 1) against cancer cell lines in combination with all of the tested nucleoside analogues. Then, to analyze the mechanism underlying the synergistic effect, we asked whether treatment with TAS1553 augments the activity of salvage pathway by measuring ara-CTP, which is an active metabolite of cytarabine. The results showed that treatment with TAS1553 significantly increased ara-CTP accumulation in MV-4-11 cells implying that TAS1553 activates nucleoside salvage pathway by inhibiting de novo nucleotide synthesis. Importantly, when analyzing the timing of treatment for the combination, prior or simultaneous treatment with TAS1553 increased ara-CTP amount more than post treatment. Consistently with in vitro result, co-administration of TAS1553 and cytarabine caused significant increase of intratumoral ara-CTP compared with cytarabine administration in MV-4-11 mouse xenograft model. Following this result, the combination of TAS1553 (100 mg/kg/day, q.d.) and cytarabine (10 mg/kg/day, 5 consecutive days) showed superior antitumor efficacy to MV-4-11 tumor than each monotherapy while the combination did not cause intolerable body weight change. Furthermore, TAS1553 also demonstrated the striking anittumor efficacy in combination with gemcitabine (20 mg/kg/day, q.wk.) on CFPAC-1 mouse xenograft model. Conclusions: TAS1553, a novel class of RNR inhibitor, has synergistic antitumor efficacy in combination with nucleoside analogues. These combination therapy could be promising therapeutic options for cancer patients. Citation Format: Takuya Hoshino, Hiroyuki Ueno, Wakako Yano, Sayaka Tsukioka, Seiji Miyahara, Takamasa Suzuki, Kazutaka Miyadera, Teruhiro Utsugi, Takeshi Sagara. TAS1553, a novel class of RNR inhibitor, demonstrates synergistic antitumor efficacy in combination with nucleoside analogues [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A063. doi:10.1158/1535-7163.TARG-19-A063

The effect of melt crystallization on inorganic hydrate for purification of crystals containing liquid and solid impurities was investigated. Melt crystallization is generally applied to purify organic crystals. In the case of inorganic crystals, it is cost-ineffective because of the higher melting point. However, some inorganic crystals, i.e., hydrate crystals, can be applied to melt crystallization because of the lower melting point. Hydrate crystals containing impurities were prepared and melt crystallization was carried out to investigate the purification mechanism on inorganic crystals. Liquid impurity in target crystals was removed by sweating and washing with melt. Solid impurity was also separated with melt flow, supported by mixing operations. It was considered that the purification mechanism is differently dependent on the state of impurity.

The objective of our study is to investigate the effect of melt crystallization on inorganic hydrate for purification of crystals including impurity. Melt crystallization is widely applied in the chemical and food industry to purify organic crystals by separating impurities inside the crystals. The target crystals are mainly organic crystals; however, some inorganic crystals are considered for purification by melt crystallization, because of having lower melting point as hydrate crystals. Therefore, we prepared hydrate crystals including impurities and carried out melt crystallization to investigate the purification mechanism on inorganic crystals. Aluminum nitrate nonahydrate was selected as purification target and strontium nitrate was selected as liquid impurity. As solid impurity, we selected barium nitrate. In conclusion, liquid impurity in target crystals was removed by sweating and washing with melt. Moreover, it was considered that the purification mechanism differs depending on the state of the impurity, and melt crystallization is an effective tool for purification the inorganic hydrate crystals.

Luminescence peak energy of amorphous hydrogenated silicon (a-Si:H) increases with excitation energy in the Urbach tail and in the higher excitation energy range the peak energy is constant. The excitation energy at which the peak energy turns from increase to constant is shown to be understood as the hopping-gap. The hopping-gap decreases with temperature as in the case of the optical bandgap. Furthermore, it is discussed by comparing with the luminescence in porous Si that the luminescence in a-Si:H may be due to the radiative recombination of electron-hole pairs in hydrogen-free Si nanostructures. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

We have developed a new thermal CVD technique for poly-SiGe thin films that meets the requirements for low-cost fabrication of post-amorphous silicon (a-Si:H) TFTs, i.e., Reactive Thermal CVD featuring a set of reactive source materials of disilane (Si 2 H 6 ) and germanium tetrafluoride (GeF 4 ). We succeeded in deposition of poly-SiGe thin films at 450°C or higher on glass substrates by this technique. And we succeeded in depositing uniform films in a thickness variation less than 5% for the entire area of 6-inch substrate. Thanks to high crystallinity of the present films at the initial stage of the film growth on the substrates, the films exhibited such high crystallinity that we could fabricate bottom-gate TFTs with very thin poly-SiGe films of 30nm deposited directly on SiO 2 /Si substrates, which showed high mobility of 8 cm2/Vs.