39 results on '"Sase, H."'
Search Results
2. Annual Changes in Some Physiological Properties of Cryptomeria Japonica Leaves from Kanto, Japan
- Author
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Takamatsu, T., Sase, H., Takada, J., Matsushita, R., Satake, Kenichi, editor, Shindo, Junko, editor, Takamatsu, Takejiro, editor, Nakano, Takanori, editor, Aoki, Shigeru, editor, Fukuyama, Tsutomu, editor, Hatakeyama, Shiro, editor, Ikuta, Kazukamasa, editor, Kawashima, Munetsugu, editor, Kohno, Yoshihisa, editor, Kojima, Satoru, editor, Murano, Kentaro, editor, Okita, Toshiichi, editor, Taoda, Hiroshi, editor, Tsunoda, Kinichi, editor, and Tsurumi, Makoto, editor
- Published
- 2001
- Full Text
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3. QA/QC activities and ecological monitoring in the Acid Deposition Monitoring Network in East Asia (EANET)
- Author
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Sase H, Nakayama S, Leong CP, Kamisako M, Luangjame J, Garivait H, Visaratana T, Kietvuttinon B, and Ueda H
- Subjects
EANET ,Acid deposition ,Soil monitoring ,Catchment ,Ozone ,Forestry ,SD1-669.5 - Abstract
An overview is presented of Quality assurance/Quality control QA/QC activities and current features of the ecological monitoring in the frame of the Acid Deposition Monitoring Network in East Asia EANET. It is stressed that standardization of the methodologies applicable for new topics, such as the catchment analysis and ozone impacts, should be investigated for future monitoring.
- Published
- 2009
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4. Role of the dwarf bamboo (Sasa) community in retaining basic cations in soil and preventing soil acidification in mountainous areas of Japan
- Author
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Takamatsu, T., Kohno, T., Ishida, K., Sase, H., Yoshida, T., and Morishita, T.
- Published
- 1997
5. Estimating transboundary transported anthropogenic sulfate deposition in Japan using the sulfur isotopic ratio
- Author
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Inomata, Y., primary, Ohizumi, T., additional, Saito, T., additional, Morohashi, M., additional, Yamashita, N., additional, Takahashi, M., additional, Sase, H., additional, Takahashi, K., additional, Kaneyasu, N., additional, Fujihara, M., additional, Iwasaki, A., additional, Nakagomi, K., additional, Shiroma, T., additional, and Yamaguchi, T., additional
- Published
- 2019
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6. Some physiological properties of Cryptomeria japonica leaves from Kanto, Japan: potential factors causing tree decline
- Author
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Takamatsu, T, Sase, H, and Takada, J
- Published
- 2001
7. Annual changes in some physiological properties of Cryptomeria japonica leaves from Kanto, Japan
- Author
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Takamatsu, T, Sase, H, Takada, J, and Matsushita, R
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contact angles ,cuticular transpiration ,Cryptomeria japonica ,Sb ,epicuticular wax - Published
- 2001
8. Air pollution impact on forests in a changing climate. In: Forests and Society Responding to Global Drivers of Change
- Author
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Lorenz M., Clarke N., Paoletti E., Bytnerowicz A., Grulke N., Lukina N., Sase H., and Staelens J.
- Abstract
Growing awareness of air pollution effects on forests has, from the early 1980s on, led to intensive forest damage research and monitoring. This has fostered air pollution control, especially in Europe and North America, and to a smaller extent also in other parts of the world. At several forest sites in these regions, there are first indications of a recovery of forest soil and tree conditions that may be attributed to improved air quality. This caused a decrease in the attention paid by politicians and the public to air pollution effects on forests. But air pollution continues to affect the structure and functioning of forest ecosystems not only in Europe and North America but even more so in parts of Russia, Asia, Latin America, and Africa. At the political level, however, attention to climate change is focussed on questions of CO2 emission and carbon sequestration. But ecological interactions between air pollution including CO2 and O3 concentrations, extreme temperatures, drought, insects, pathogens, and fire, as well as the impact of ecosystem management practices, are still poorly understood. Future research should focus on the interacting impacts on forest trees and ecosystems. The integrative effects of air pollution and climatic change, in particular elevated O3, altered nutrient, temperature, water availability, and elevated CO2, will be key issues for impact research. An important improvement in our understanding might be obtained by the combination of long-term multidisciplinary experiments with ecosystem-level monitoring, and the integration of the results with ecosystem modelling within a multiple-constraint framework.
- Published
- 2010
9. Atmospheric deposition versus rock weathering in the control of streamwater chemistry in a tropical rain-forest catchment in Malaysian Borneo
- Author
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Yamashita, N., Sase, H., Kobayashi, R., Peng, Leong Kok, Hanapi, Jamal Mohd, Uchiyama, S., Urban, S., Ying-Ying, Toh, Muhamad, Maznorizan, Gidiman, Jikos, Chappell, Nick A., Yamashita, N., Sase, H., Kobayashi, R., Peng, Leong Kok, Hanapi, Jamal Mohd, Uchiyama, S., Urban, S., Ying-Ying, Toh, Muhamad, Maznorizan, Gidiman, Jikos, and Chappell, Nick A.
- Abstract
Uncertainty about the H+ buffering capacity in tropical rain forest limits our ability to predict the future effect of anthropogenic deposition on the streamwater chemistry. Export ofmajor ions to the stream and the ion-fluxes via rainfall, throughfall, litter-leachate and soil-water pathways were observed to examine the source of streamwater nutrients in a small catchment in Sabah, Malaysia. The streamwater and the ion-fluxes were measured for 3.75 and 2 y, respectively, by collecting water twice a month and setting ion-exchange-resin columns. Streamwater pH ranged from 6.5 to 7.6 and was not sensitive to water discharge controlling base cations. The NO3--N, Ca2+ and Mg2+ fluxes were low in atmospheric depositions (0.6, 0.5 and 0.3 kg ha−1 y−1, respectively) andmarkedly increased in litter layer. The NO3− flux decreased drastically from subsoil (70 kg ha−1 y−1) to the stream (1.4 kg ha−1 y−1) whereas the Ca2+ and Mg2+ fluxes were not different between subsoil (38 and 18 kg ha−1 y−1) and stream (30 and 15 kg ha−1 y−1). Neutral pH in tropical streams was mainly due to the base cation leaching with deep chemical weathering in deeper strata, and a rapid decrease in NO3− leaching from the subsoil to the stream.
- Published
- 2014
10. The EANET challenges on catchment-scale monitoring in Asian forests
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Sase, H., Yamashita, N., Luangjame, J., Garivait, H., Visaratana, T., Kietvuttinon, B., Hongthong, B., Urban, S., Leong, C. P., Toh, Y.Y., Majid, N.M., Sanusi, A., Ahmed, O.H., Gandaseca, S., Chappell, Nicholas, Ohta, S., Shindo, J., Hayashi, K., Matsuda, K., Sase, H., Yamashita, N., Luangjame, J., Garivait, H., Visaratana, T., Kietvuttinon, B., Hongthong, B., Urban, S., Leong, C. P., Toh, Y.Y., Majid, N.M., Sanusi, A., Ahmed, O.H., Gandaseca, S., Chappell, Nicholas, Ohta, S., Shindo, J., Hayashi, K., and Matsuda, K.
- Abstract
Atmospheric deposition is still one of the major environmental issues in Asia. The joint research projects for catchment-scale analysis have been conducted in a tropical rainforest (Danum Valley, Malaysia), tropical seasonal forest (Sakaerat, Thailand) and temperate coniferous forest (Kajikawa, Japan) for future monitoring in EANET. In Kajikawa site, the possibility of nitrogen saturation was suggested by the largest level of nitrogen deposition. In tropical forests, acid buffering capacity of the ecosystems was higher in Danum Valley site than in Sakaerat site. The data in different climates will be useful for biogeochemical model as it may contribute to atmospheric management.
- Published
- 2011
11. The EANET challenge on the catchment-scale analysis for the future integrated monitoring.
- Author
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Sase, H., Luangjame, J., Garivait, H., Urban, S., Yamashita, N., Nakahara, O., Kietvuttinon, B., Visaratana, T., Kobayashi, R., Takahashi, M., Hakamata, T., Chappell, N. A., Leong, C. P., Ohta, S., Shindo, J., Hayashi, K., Matsuda, K., Sase, H., Luangjame, J., Garivait, H., Urban, S., Yamashita, N., Nakahara, O., Kietvuttinon, B., Visaratana, T., Kobayashi, R., Takahashi, M., Hakamata, T., Chappell, N. A., Leong, C. P., Ohta, S., Shindo, J., Hayashi, K., and Matsuda, K.
- Abstract
Integrated monitoring of atmospheric deposition, soil, vegetation, and inland water is required to evaluate effects of atmospheric deposition on ecosystems qualitatively and quantitatively. For this purpose, the Acid Deposition Monitoring Network in East Asia (EANET) has promoted case studies on catchment-scale analysis in several forest types of the East Asian region, including a tropical seasonal forest in Sakaerat, Thailand; a tropical rainforest in Danum Valley, Malaysia; and a temperate coniferous forest in Kajikawa, Japan. The similar catchment-scale monitoring has also been conducted in the catchment of Lake Ijira in Japan, one of the EANET sites. Several factors, including climate, hydrology, geology, soil, vegetation, and atmospheric deposition may affect stream water chemistry. In the tropical catchments, stream water chemistry at the Sakaerat site changed significantly from the beginning to middle of wet season, reflecting the distinct climatic seasonality, while that at the Danum Valley site was regulated mainly by water discharge. In the temperate catchments, atmospheric deposition may have a larger role; acidification of soil and/or stream water has been seen with high sulfur and nitrogen depositions. Data and experience from these case studies will also be informative for development of biogeochemical model applicable to the East Asian catchments.
- Published
- 2010
12. Effects of sensor noise in digital signal processing of the three-point method
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Fujimaki, K, primary, Sase, H, additional, and Mitsui, K, additional
- Published
- 2007
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13. Long-term Trends in Surface Water Quality of Five Lakes in Japan
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Yamada, T., primary, Inoue, T., additional, Fukuhara, H., additional, Nakahara, O., additional, Izuta, T., additional, Suda, R., additional, Takahashi, M., additional, Sase, H., additional, Takahashi, A., additional, Kobayashi, H., additional, Ohizumi, T., additional, and Hakamata, T., additional
- Published
- 2007
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14. Long-term Trends in Surface Water Quality of Five Lakes in Japan.
- Author
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Brimblecombe, Peter, Hara, Hiroshi, Houle, Daniel, Novak, Martin, Yamada, T., Inoue, T., Fukuhara, H., Nakahara, O., Izuta, T., Suda, R., Takahashi, M., Sase, H., Takahashi, A., Kobayashi, H., Ohizumi, T., and Hakamata, T.
- Abstract
Since 1983, the Ministry of the Environment of Japan has conducted nation-wide acid deposition surveys. To investigate the effects of acid deposition on surface water, we used the nonparametric Mann—Kendall test to find temporal trends in pH, alkalinity, and electrical conductivity (EC) in more than 10 years of data collected from five lakes and their catchments (Lake Kuttara: northernmost; Lake Kamakita: near Tokyo; Lake Ijira: central; Lake Banryu: western; and Lake Unagiike: southernmost). The pH of Lake Ijira water has declined slightly since the mid-1990s, corresponding with the downward trends seen in the pH and alkalinity of the river water flowing into the lake. There were significant upward trends in the EC of both the lake and stream water; the same trends were also found for NO3− concentrations. These trends show evidence of acidification due to atmospheric deposition, and this is the first such finding in Japan based on significant long-term trends. Lake Ijira is located about 40 km north of the Chukyo industrial area near Nagoya. The annual depositions of H+, nss-SO42−, and NO3− in Lake Ijira were among the highest of all deposition monitoring sites, suggesting that this is the main cause of the significant acidification observed in Lake Ijira. No significant trends suggesting acidification were observed in any of the other lake catchments in spite of the significant upward trends in EC. Upward trends in pH and alkalinity at Lake Banryu and upward trends in alkalinity at Lake Kamakita were detected, but no change in pH or alkalinity at Lake Kuttara and Lake Unagiike was observed. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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15. Functional and Sensory Properties of Meat Emulsions Produced by using Enzymatically Modified Gelatin
- Author
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SASE, H., primary, WATANABE, M., additional, ARAI, S., additional, and OGAWA, Y., additional
- Published
- 1987
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16. High speed image data compression processor for Advanced Land Observing Satellite (ALOS)
- Author
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Hihara, H., primary, Sato, M., additional, Fukasawa, K., additional, Sase, H., additional, Osawa, Y., additional, and Ito, N., additional
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17. High speed image data compression processor for Advanced Land Observing Satellite (ALOS).
- Author
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Hihara, H., Sato, M., Fukasawa, K., Sase, H., Osawa, Y., and Ito, N.
- Published
- 2002
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18. Role of the dwarf bamboo (Sasa) community in retaining basic cationsin soil and preventing soil acidification in mountainous areas of Japan
- Author
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Sase, H., Takamatsu, T., Yoshida, T., Morishita, T., Kohno, T., and Ishida, K.
- Subjects
SOIL acidity ,SOIL science - Abstract
Adjacent plots (1 m
2 ) with and without communities of dwarf bamboo (Sasa), i.e. Sasa- and ref-plots, were selected in mountainous areas, which were relatively low in soil buffer capacity. The following parameters; were studied: chemical properties of surface (0--30 cm) soil (at 6 sites), elemental abundances in the soil-Sasa ecosystem (at 6 sites), effect of artificial acid rain on the above two parameters (at 1 site), and chemical properties of throughfall and stemflow of Sasa (at 2 sites including one on a plain). Average values of pH(H2 O), base saturation and the ratio of exchangeable(K+Mg+Ca)/exchangeable Al in surface soil were 4.35 q0.53, 25.2 q14.3% and 0.41 q0.29, respectively, in Sasa-plots and 4.26 q0.63, 20.0 q9.6%, and 0.28 q0.13, respectively, in ref-plots. Though not significant, all soil parameters had higher values in Sasa-plots, i.e. Deltax = ca. 0.1 unit, 5% and 0.13, respectively. When the abundance ofelements (exchangeable cations in soil of 30 cm depth plus elements in litter and Sasa biomass) in the ecosystem was compared between the two plots, K (and often other basic cations) was higher in Sasa-plots than in ref-plots, whereas Al was lower. Artificial acid rain (1.5 L of 0.05 M H2 SO4 applied monthly for 10 months) induced a reduction of Na, K, Mg and Ca in a ref-plot, but in aSasa-plot only Na and K were reduced whereas Mg and Ca were completely retained. The composite samples of throughfall and stemflow of Sasa were ca. 0.5 higher in pH and richer in K, Mg and Ca than the ambient precipitation. The amounts (equivalents) of elements released by Sasa were in the order K > Ca > Mg. It was determined that about 87% and 98% of K, 76% and 87% of Ca, and 39% and 93% of Mg were of Sasa origin in the composite samples at a mountainous site (cambisol soil type) and a plain site (andosol soil type), respectively. Sasa communities may have a significant role in retention of basic cations in s [ABSTRACT FROM AUTHOR]- Published
- 1997
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19. Impact of seasonality and forest stand age on ion deposition in rehabilitated forests.
- Author
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Ibrahim MH, Jaafar S, Yamashita N, and Sase H
- Abstract
This study examines the critical interaction between seasonal precipitation variability and forest maturity in determining ion deposition patterns in rehabilitated forest ecosystems. This research was conducted in rehabilitated forest sites in Bintulu, Sarawak, Malaysia that had ecologically similar plant distribution, species, and age in each planting area. This facilitated the standardization of rainfall deposition in the different study plots which streamlined the study of these specific facets of ecosystem dynamics. The goal is to understand how seasonal changes and the age of the forest influence the chemical composition of the flux that relates to the movement and deposition of nutrients through the forest ecosystem. This flux is a key factor in the health of the forest ecosystem and nutrient cycling. Using ion exchange resin (IER) samplers, we accurately measured and compared the deposition of different ions (Ca
2+ , Na+ , Fe2+ , Cu2+ , NO3 - , NH4 + and SO4 2- ) across different seasons and forest ages. The deposition of Ca2+ and NH₄+ was significantly lower in the low-precipitation season than in the high-precipitation season in all forest stands, regardless of the year they were established (1996, 1999, 2002, 2005, and 2009). In contrast, ions such as Na+ , Fe2+ , Cu2+ , NO3 - and SO4 2- showed no clear seasonal fluctuations. In addition, the study shows that through-fall in forest stands from 2002, 2005 and 2009 had higher concentrations of Ca2+ in both seasons than in 1996 and 1999. Interestingly, forest stands from 2009 and 2002 had elevated levels of Na+ and SO₄2- in seasons with low precipitation, while stands from 1996 had higher levels in seasons with high precipitation. Our results emphasize the crucial role of precipitation amount and canopy age in determining ion deposition in forest ecosystems. By demonstrating the significant influence of precipitation seasonality and forest maturity on the chemical composition of throughfall, this study contributes to a deeper understanding of nutrient dynamics in developing forest landscapes and provides valuable insights for ecological restoration measures., Competing Interests: The author declares that there is no conflict of interest., (© 2024 The Author(s). Plant‐Environment Interactions published by New Phytologist Foundation and John Wiley & Sons Ltd.)- Published
- 2024
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20. Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display.
- Author
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Kage M, Hayashi R, Matsuo A, Tamiya M, Kuramoto S, Ohara K, Irie M, Chiyoda A, Takano K, Ito T, Kotake T, Takeyama R, Ishikawa S, Nomura K, Furuichi N, Morita Y, Hashimoto S, Kawada H, Nishimura Y, Nii K, Sase H, Ohta A, Kojima T, Iikura H, Tanada M, and Shiraishi T
- Subjects
- Structure-Activity Relationship, Humans, Molecular Structure, Animals, Dose-Response Relationship, Drug, Peptides, Cyclic chemistry, Peptides, Cyclic pharmacology, Peptides, Cyclic chemical synthesis, Peptides, Cyclic pharmacokinetics, RNA, Messenger metabolism, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism
- Abstract
Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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21. Patterns and drivers of atmospheric inorganic nitrogen deposition in Northeast Asia.
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Mgelwa AS, Zhu F, Huang D, Song L, Wang Y, Gurmesa GA, Wang A, Liu M, Huang S, Qiu Q, Sase H, Zhu W, and Fang Y
- Subjects
- Ecosystem, Nitrogen analysis, China, Environmental Monitoring, Air Pollutants analysis, Ammonium Compounds
- Abstract
Elevated nitrogen (N) deposition due to intensified emissions of NH
3 and NOx is a global problem with profound consequences on living organisms and the environment. Although N emission rates are currently considered to be high in East Asia, reports on the current N deposition level and composition are still limited, especially in northeastern China, where official N deposition monitoring sites are unavailable. This limits our understanding of the spatio-temporal N deposition patterns and their influencing factors at regional to continental scales. Here, we used data collected mostly during 2019 at 38 sites, comprising 7 sites in northeastern China and 31 EANET (Acid Deposition Monitoring Network in East Asia) sites in middle and east Russia, Mongolia, central and southern China, South Korea and Japan to explore the spatial-seasonal variations and drivers of ammonium and nitrate deposition across the Northeast Asia. Total bulk inorganic N (TIN) deposition was 3.7-24.5 kg N ha-1 yr-1 and NH4 + -N/NO3 - -N ratio in the TIN was 0.8-2.8 in northeastern China. The bulk/wet TIN deposition averaged 7.5 kg N ha-1 yr-1 (predominantly in the form of ammonium-N: NH4 + -N/NO3 - -N = 1.4) over the Northeast Asia region, with the highest rates being observed in northeastern China (11.6), as well as central and southern China (10.7), followed by east Russia, South Korea and Japan (5.6), and the lowest in middle Russia and Mongolia (1.5). This regional bulk/wet TIN deposition level is about twice of the wet TIN deposition level in Europe and the United States. The TIN deposition in summer and spring was 45-467% higher than in autumn and winter. Out of the ten land uses considered, only agricultural and urban land uses significantly positively correlated with NH4 + -N and NO3 - -N deposition rates across all monitored sites. This study suggests that the ongoing agricultural and urban expansions are likely to enhance N deposition and its associated effects across global ecosystems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2024
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22. Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.
- Author
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Ohta A, Tanada M, Shinohara S, Morita Y, Nakano K, Yamagishi Y, Takano R, Kariyuki S, Iida T, Matsuo A, Ozeki K, Emura T, Sakurai Y, Takano K, Higashida A, Kojima M, Muraoka T, Takeyama R, Kato T, Kimura K, Ogawa K, Ohara K, Tanaka S, Kikuchi Y, Hisada N, Hayashi R, Nishimura Y, Nomura K, Tachibana T, Irie M, Kawada H, Torizawa T, Murao N, Kotake T, Tanaka M, Ishikawa S, Miyake T, Tamiya M, Arai M, Chiyoda A, Akai S, Sase H, Kuramoto S, Ito T, Shiraishi T, Kojima T, and Iikura H
- Subjects
- Peptides, Cyclic chemistry
- Abstract
Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol). In this study, we validated a new methodology to create oral drugs beyond the rule of 5 for intracellular tough targets by elucidating structural features and physicochemical properties for drug-like cyclic peptides and developing library technologies to afford highly N -alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.
- Published
- 2023
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23. Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor.
- Author
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Tanada M, Tamiya M, Matsuo A, Chiyoda A, Takano K, Ito T, Irie M, Kotake T, Takeyama R, Kawada H, Hayashi R, Ishikawa S, Nomura K, Furuichi N, Morita Y, Kage M, Hashimoto S, Nii K, Sase H, Ohara K, Ohta A, Kuramoto S, Nishimura Y, Iikura H, and Shiraishi T
- Subjects
- Humans, Caco-2 Cells, Peptides, Cyclic chemistry, Molecular Conformation, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Peptides pharmacology, Peptides metabolism
- Abstract
Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including C log P can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10
-6 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide's main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski's rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.- Published
- 2023
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24. Seasonal variations in the amount of black carbon particles deposited on the leaf surfaces of nine Japanese urban greening tree species and their related factors.
- Author
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Takahashi K, Ohta A, Sase H, Murao N, Takada K, Yamaguchi M, Nakaba S, Watanabe M, and Izuta T
- Subjects
- Biodegradation, Environmental, Carbon, Plant Leaves, Seasons, Water, Japan, Trees, Soot
- Abstract
As black carbon (BC) particles can be deposited on the leaf surfaces, urban greening is considered to be effective in purifying urban air. However, little information on the seasonal variations in the amount of BC particles deposited on the leaf surfaces (BC amount on the leaves) is available in Japanese urban greening tree species. Therefore, we investigated seasonal variations in the BC amount on the leaves of evergreen ( Quercus glauca , Quercus myrsinaefolia , Osmanthus fragrans and Ilex rotunda ) and deciduous ( Zelkova serrata , Styrax japonica , Magnolia kobus , Cornus kousa and Cornus florida ) broad-leaved tree species. The BC amount on the leaves tended to increase from April for different periods, and then reached a saturated state in the tree species, excluding M. kobus . In the 4 evergreen broad-leaved trees, the seasonal variation was positively correlated with the atmospheric concentration of BC particle. In the 5 deciduous broad-leaved trees, the seasonal variation was negatively and positively correlated with the water-repellence (water droplet contact angle) and the amount of epicuticular wax on the leaf surface, respectively. Therefore, the BC amounts on the leaves of evergreen and deciduous broad-leaved urban tree species are considered to be mainly regulated by environmental factors and leaf surface characteristics, respectively.
- Published
- 2023
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25. Relationship between the amount of black carbon particles deposited on the leaf surface and leaf surface traits in nine urban greening tree species.
- Author
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Ohta A, Takahashi K, Sase H, Murao N, Takada K, Yamaguchi M, Murakami H, Nakaba S, Watanabe M, Mizukawa K, Takada H, and Izuta T
- Subjects
- Biodegradation, Environmental, Plant Leaves chemistry, Seedlings chemistry, Carbon analysis, Environmental Monitoring, Particulate Matter analysis, Trees, Air Pollutants analysis
- Abstract
To select urban greening tree species suitable for the purification of the atmosphere polluted by black carbon (BC) particles, it is necessary to clarify the determinants of the amount of BC particles deposited on the tree leaves. In the present study, we investigated the relationship between the amount of BC particles that were deposited from the atmosphere and firmly adhered to the leaf epicuticular wax, and leaf surface traits in seedlings of nine tree species grown for two years under natural conditions (Fuchu, Tokyo, Japan). There was a significant interspecific difference in the maximum amount of BC particles deposited on the leaf surface, and the order was as follows: Ilex rotunda > Cornus florida > Osmanthus fragrans > Cornus kousa > Quercus glauca ≒ Quercus myrsinifolia > Magnolia kobus ≒ Zelkova serrata ≒ Styrax japonicus . In the nine tree species, significant highly positive correlations were observed between the amount of BC particles deposited on the leaf surface, and the hydrophobicity of leaf epicuticular wax determined by its chemical composition. Therefore, we concluded that the hydrophobicity of leaf epicuticular wax is an important determinant of the amount of BC particles deposited on the leaf surface of urban greening tree species.
- Published
- 2023
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26. Assessing critical loads and exceedances for acidification and eutrophication in the forests of East and Southeast Asia: A comparison with EANET monitoring data.
- Author
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Yamashita N, Sase H, and Kurokawa J
- Subjects
- Eutrophication, Forests, Trees, Nitrogen analysis, Soil, Sulfur analysis, Nitrogen Oxides, Hydrogen-Ion Concentration, Asia, Southeastern, Water, Environmental Monitoring, Ecosystem, Nitrates
- Abstract
Spatial variations in sulfur (S) and nitrogen (N) deposition have changed in East and Southeast Asia in recent decades. Nevertheless, in this region, including the tropics, regional-scale assessments of the long-term risk of acidification and eutrophication (N saturation) for terrestrial ecosystems using a critical load approach have not been updated since 2001. To evaluate future risks, maps of critical loads and exceedances were updated using recently acquired spatial datasets of soil properties, soil minerals, climate, tree plantations, and the annual S and N depositions estimated using the Community Multiscale Air Quality (CMAQ) model. The resulting maps were verified using data on long-term trends in soil pH and nitrate concentration in surface water acquired by the Acid Deposition Monitoring Network in East Asia (EANET). It was found that N deposition exceeded the critical load for eutrophication not only in East Asia but also in some parts of the tropical monsoon and humid regions in Southeast Asia, whereas S deposition partly exceeded the critical load for soil acidification in China and small parts of the tropical monsoon region. The high-risk areas for eutrophication coincided well with the EANET sites, where the increase in nitrate concentration in the surface water was significant over the last 20 years. Hence, the estimated map of the critical load exceedance for eutrophication is more plausible for assessing the risk in East and Southeast Asia than that for acidification, although the critical load exceedance for acidification would be sufficiently significant as an updated risk map based on the latest input values. This update also suggests that increased N deposition around megacities, water discharge, and tree plantations may play an important role in the spatial variability of eutrophication risks in the tropics of Southeast Asia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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27. Strategic roadmap to assess forest vulnerability under air pollution and climate change.
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De Marco A, Sicard P, Feng Z, Agathokleous E, Alonso R, Araminiene V, Augustatis A, Badea O, Beasley JC, Branquinho C, Bruckman VJ, Collalti A, David-Schwartz R, Domingos M, Du E, Garcia Gomez H, Hashimoto S, Hoshika Y, Jakovljevic T, McNulty S, Oksanen E, Omidi Khaniabadi Y, Prescher AK, Saitanis CJ, Sase H, Schmitz A, Voigt G, Watanabe M, Wood MD, Kozlov MV, and Paoletti E
- Subjects
- Ecosystem, Forests, Trees, Air Pollution adverse effects, Climate Change
- Abstract
Although it is an integral part of global change, most of the research addressing the effects of climate change on forests have overlooked the role of environmental pollution. Similarly, most studies investigating the effects of air pollutants on forests have generally neglected the impacts of climate change. We review the current knowledge on combined air pollution and climate change effects on global forest ecosystems and identify several key research priorities as a roadmap for the future. Specifically, we recommend (1) the establishment of much denser array of monitoring sites, particularly in the South Hemisphere; (2) further integration of ground and satellite monitoring; (3) generation of flux-based standards and critical levels taking into account the sensitivity of dominant forest tree species; (4) long-term monitoring of N, S, P cycles and base cations deposition together at global scale; (5) intensification of experimental studies, addressing the combined effects of different abiotic factors on forests by assuring a better representation of taxonomic and functional diversity across the ~73,000 tree species on Earth; (6) more experimental focus on phenomics and genomics; (7) improved knowledge on key processes regulating the dynamics of radionuclides in forest systems; and (8) development of models integrating air pollution and climate change data from long-term monitoring programs., (© 2022 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)
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- 2022
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28. Development of science and policy related to acid deposition in East Asia over 30 years.
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Akimoto H, Sato K, Sase H, Dong Y, Hu M, Duan L, Sunwoo Y, Suzuki K, and Tang X
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- Environmental Monitoring, Asia, Eastern, Nitrogen analysis, Policy, Soil, Sulfur analysis, Water, Air Pollutants analysis, Environmental Pollutants
- Abstract
Scientific and public interest in acid deposition and its ecological impacts have increased throughout 1990s in East Asia (Northeast and Southeast Asia). After being established in 2001, the Acid Deposition Monitoring Network in East Asia (EANET) celebrates the 20th anniversary in 2021, and is now being expanded in scope reflecting the shifting social concern from acid deposition to broader air quality and climate change in recent years. This paper reviews the past 30 years of development of scientific research and policy related to acid deposition in East Asia. Since the onset of the twenty-first century, East Asia has had the highest SO
2 and NOx emissions in the world by continents, with substantial economic developmental inequality among countries. An overview of studies on sulfur and nitrogen deposition, the acidification of inland water and forest soil, and forest decline reveal that although limited acidification of inland water and forest soils have been documented, no decline in the populations of fish and other aquatic biota has been reported in East Asia. After a review of policy-oriented modeling studies on source receptor relationships and the critical loads of sulfur and nitrogen in East Asia, the history of EANET and its success and challenges are discussed. Finally, the importance of epistemic communities as the interface between science and policy in the region is discussed. Regional governance and cooperation are essential for reducing the emission of greenhouse gases, especially short-lived climate pollutants and atmospheric pollutants to realize the co-benefits of global climate change mitigation and improved air quality., (© 2022. The Author(s) under exclusive licence to Royal Swedish Academy of Sciences.)- Published
- 2022
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29. Air pollution monitoring and tree and forest decline in East Asia: A review.
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Takahashi M, Feng Z, Mikhailova TA, Kalugina OV, Shergina OV, Afanasieva LV, Heng RKJ, Majid NMA, and Sase H
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- China, Ecosystem, Asia, Eastern, Forests, Japan, Mongolia, Republic of Korea, Russia, Siberia, Trees, Air Pollutants analysis, Air Pollution
- Abstract
Air pollution and atmospheric deposition have adverse effects on tree and forest health. We reviewed studies on tree and forest decline in Northeast and Southeast Asia, Siberia, and the Russian Far East (hereafter referred to as East Asia). This included studies published in domestic journals and languages. We identified information about the locations, causes, periods, and tree species exhibiting decline. Past air pollution was also reviewed. Most East Asian countries show declining trends in SO
2 concentration in recent years, although Mongolia and Russia show increasing trends. Ozone (O3 ) concentrations are stable or gradually increasing in the East Asia region, with high maxima. Wet nitrogen (N) deposition was high in China and tropical countries, but low in Russia. The decline of trees and forests primarily occurred in the mid-latitudes of Japan, Korea, China, and Russia. Long-term large N deposition resulted in the N saturation phenomenon in Japan and China, but no clear forest health response was observed. Thereafter, forest decline symptoms, suspected to be caused by O3 , were observed in Japan and China. In East Russia, tree decline occurred around industrial centers in Siberia. Haze events have been increasing in tropical and boreal forests, and particulate matter inhibits photosynthesis. In recent years, chronically high O3 concentrations, in conjunction with climate change, are likely have adverse effects on tree physiology. The effects of air pollution and related factors on tree decline are summarized. Recently, the effects of air pollution on tree decline have not been apparent under the changing climate, however, monitoring air pollution is indispensable for identifying the cause of tree decline. Further economic growth is projected in Southeast Asia and therefore, the monitoring network should be expanded to tropical and boreal forest zones. Countermeasures such as restoring urban trees and rural forests are important for ensuring future ecosystem services., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2020
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30. Selective TRK Inhibitor CH7057288 against TRK Fusion-Driven Cancer.
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Tanaka H, Sase H, Tsukaguchi T, Hasegawa M, Tanimura H, Yoshida M, Sakata K, Fujii T, Tachibana Y, Takanashi K, Higashida A, Hasegawa K, Ono Y, Oikawa N, and Mio T
- Subjects
- Animals, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Female, Humans, Mice, Inbred BALB C, Mice, Nude, Mutation genetics, Protein Kinases chemistry, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Benzofurans pharmacology, Neoplasms pathology, Oncogene Proteins, Fusion metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinases metabolism
- Abstract
Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. Strong in vivo tumor growth inhibition was observed in subcutaneously implanted xenograft tumor models of TRK fusion-positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induced tumor regression and improved event-free survival. Recently, resistant mutations in the kinase domain of TRK have been reported in patients who show disease progression after treatment with the TRK inhibitors now under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against one of these resistant mutants as it did to wild-type TRK. An X-ray crystal structure of the TRKA and CH7057288 complex supported the activity against the mutant. In addition, gene expression analysis revealed that CH7057288 suppressed MAPK and E2F pathways as downstream signaling of TRK fusion. Therefore, CH7057288 could be a promising therapeutic agent for TRK fusion-positive cancer., (©2018 American Association for Cancer Research.)
- Published
- 2018
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31. Acquired JHDM1D-BRAF Fusion Confers Resistance to FGFR Inhibition in FGFR2 -Amplified Gastric Cancer.
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Sase H, Nakanishi Y, Aida S, Horiguchi-Takei K, Akiyama N, Fujii T, Sakata K, Mio T, Aoki M, and Ishii N
- Subjects
- Animals, Cell Line, Tumor, Cell Survival drug effects, Comparative Genomic Hybridization, Humans, Stomach Neoplasms drug therapy, Stomach Neoplasms pathology, Drug Resistance, Neoplasm genetics, Gene Amplification, Jumonji Domain-Containing Histone Demethylases genetics, Oncogene Proteins, Fusion genetics, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf genetics, Receptor, Fibroblast Growth Factor, Type 2 genetics, Stomach Neoplasms genetics
- Abstract
FGFR2 gene is frequently amplified in gastric cancer. Recently, targeting FGFR2 has drawn attention as a form of gastric cancer therapy, and FGFR-selective inhibitors have shown promising efficacy in clinical studies. Because overcoming acquired resistance is a common problem with molecular targeting drugs, we investigated a resistant mechanism of FGFR inhibitors using the gastric cancer cell line SNU-16, which harbors FGFR2 amplification. We established single-cell clones of FGFR inhibitor-resistant SNU-16 (AZD-R) by continuous exposure to AZD4547, a selective FGFR inhibitor. To screen the genetic alterations acquired in AZD-R, we ran a comparative genomic hybridization assay and found an amplification of Chr7q34 region. The chromosomal breakpoints were located between the 12th and the 13th exon of jumonji C domain containing histone demethylase 1 homolog D ( JHDM1D ) and between the 3rd and the 4th exon of BRAF We sequenced cDNA of the AZD-R clones and found fusion kinase JHDM1D-BRAF , which has previously been identified in primary ovarian cancer. Because JHDM1D-BRAF fusion lacks a RAS-binding domain, the dimerization of JHDM1D-BRAF was enhanced. A cell growth inhibition assay using MEK inhibitors and RAF-dimer inhibitors indicated the dependence of AZD-R clones for growth on the MAPK pathway. Our data provide a clinical rationale for using a MEK or RAF dimer inhibitor to treat FGFR2 -amplified gastric cancer patients who have acquired resistance through the JHDN1D-BRAF fusion. Mol Cancer Ther; 17(10); 2217-25. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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32. ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor.
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Nakanishi Y, Mizuno H, Sase H, Fujii T, Sakata K, Akiyama N, Aoki Y, Aoki M, and Ishii N
- Subjects
- Cell Line, Tumor, Cell Proliferation drug effects, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Humans, MAP Kinase Signaling System drug effects, Neoplasms pathology, Phosphorylation, Proto-Oncogene Proteins c-akt biosynthesis, Receptors, Fibroblast Growth Factor antagonists & inhibitors, Benzimidazoles administration & dosage, Neoplasm Proteins biosynthesis, Neoplasms drug therapy, Neoplasms genetics, Pyrazoles administration & dosage, Receptors, Fibroblast Growth Factor biosynthesis
- Abstract
Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. FGFR and MEK inhibition produced similar expression patterns, and the extracellular signal-regulated kinase (ERK) gene signature was altered in several FGFR inhibitor-sensitive cell lines. Consistent with these findings, CH5183284/Debio 1347 suppressed phospho-ERK in every tested FGFR inhibitor-sensitive cell line. Because the mitogen-activated protein kinase (MAPK) pathway functions downstream of FGFR, we searched for a pharmacodynamic marker of FGFR inhibitor efficacy in a collection of cell lines with the ERK signature and identified dual-specificity phosphatase 6 (DUSP6) as a candidate marker. Although a MEK inhibitor suppressed the MAPK pathway, most FGFR inhibitor-sensitive cell lines are insensitive to MEK inhibitors and we found potent feedback activation of several pathways via FGFR. We therefore suggest that FGFR inhibitors exert their effect by suppressing ERK signaling without feedback activation. In addition, DUSP6 may be a pharmacodynamic marker of FGFR inhibitor efficacy in FGFR-addicted cancers., (©2015 American Association for Cancer Research.)
- Published
- 2015
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33. The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor.
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Nakanishi Y, Akiyama N, Tsukaguchi T, Fujii T, Sakata K, Sase H, Isobe T, Morikami K, Shindoh H, Mio T, Ebiike H, Taka N, Aoki Y, and Ishii N
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Humans, Immunohistochemistry, Male, Mice, Random Allocation, Rats, Rats, Wistar, Signal Transduction, Transfection, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Benzimidazoles pharmacology, Pyrazoles pharmacology, Receptors, Fibroblast Growth Factor antagonists & inhibitors, Receptors, Fibroblast Growth Factor genetics
- Abstract
The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family displayed clinical benefits in cohorts of patients with FGFR genetic alterations. However, to achieve more potent and prolonged activity in such populations, a selective FGFR inhibitor is still needed. Here, we report the identification of CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chemical scaffold. By interacting with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 displayed preferential antitumor activity against cancer cells with various FGFR genetic alterations in a panel of 327 cancer cell lines and in xenograft models. Because of its unique binding mode, CH5183284/Debio 1347 can inhibit FGFR2 harboring one type of the gatekeeper mutation that causes resistance to other FGFR inhibitors and block FGFR2 V564F-driven tumor growth. CH5183284/Debio 1347 is under clinical investigation for the treatment of patients harboring FGFR genetic alterations., (©2014 American Association for Cancer Research.)
- Published
- 2014
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34. Identification of targets of Prox1 during in vitro vascular differentiation from embryonic stem cells: functional roles of HoxD8 in lymphangiogenesis.
- Author
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Harada K, Yamazaki T, Iwata C, Yoshimatsu Y, Sase H, Mishima K, Morishita Y, Hirashima M, Oike Y, Suda T, Miura N, Watabe T, and Miyazono K
- Subjects
- Angiopoietin-2 genetics, Animals, Cells, Cultured, Embryonic Stem Cells metabolism, Endothelium, Lymphatic cytology, Endothelium, Lymphatic embryology, Endothelium, Lymphatic metabolism, Endothelium, Vascular cytology, Endothelium, Vascular embryology, Endothelium, Vascular metabolism, Forkhead Transcription Factors genetics, Homeodomain Proteins genetics, Humans, Lymphatic Vessels cytology, Lymphatic Vessels embryology, Lymphatic Vessels metabolism, Mice, Mice, Inbred BALB C, Transcription Factors genetics, Tumor Suppressor Proteins genetics, Angiopoietin-2 metabolism, Cell Differentiation, Embryonic Stem Cells cytology, Forkhead Transcription Factors metabolism, Homeodomain Proteins metabolism, Lymphangiogenesis, Transcription Factors metabolism, Tumor Suppressor Proteins metabolism
- Abstract
During lymphatic development, Prox1 plays central roles in the differentiation of blood vascular endothelial cells (BECs) into lymphatic endothelial cells (LECs), and subsequently in the maturation and maintenance of lymphatic vessels. However, the molecular mechanisms by which Prox1 elicits these functions remain to be elucidated. Here, we identified FoxC2 and angiopoietin-2 (Ang2), which play important roles in the maturation of lymphatic vessels, as novel targets of Prox1 in mouse embryonic-stem-cell-derived endothelial cells (MESECs). Furthermore, we found that expression of HoxD8 was significantly induced by Prox1 in MESECs, a finding confirmed in human umbilical vein endothelial cells (HUVECs) and human dermal LECs (HDLECs). In mouse embryos, HoxD8 expression was significantly higher in LECs than in BECs. In a model of inflammatory lymphangiogenesis, diameters of lymphatic vessels of the diaphragm were increased by adenovirally transduced HoxD8. We also found that HoxD8 induces Ang2 expression in HDLECs and HUVECs. Moreover, we found that HoxD8 induces Prox1 expression in HUVECs and that knockdown of HoxD8 reduces this expression in HDLECs, suggesting that Prox1 expression in LECs is maintained by HoxD8. These findings indicate that transcriptional networks of Prox1 and HoxD8 play important roles in the maturation and maintenance of lymphatic vessels.
- Published
- 2009
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35. VEGFR2-PLCgamma1 axis is essential for endothelial specification of VEGFR2+ vascular progenitor cells.
- Author
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Sase H, Watabe T, Kawasaki K, Miyazono K, and Miyazawa K
- Subjects
- Animals, Cell Differentiation, Cell Survival, Endothelial Cells cytology, Enzyme Activation, Humans, Intracellular Space metabolism, Mice, Models, Biological, Mutant Proteins chemistry, Mutant Proteins metabolism, Phenylalanine metabolism, Phosphotyrosine metabolism, Protein Structure, Tertiary, Recombinant Fusion Proteins metabolism, Signal Transduction, Vascular Endothelial Growth Factor Receptor-2 chemistry, Blood Vessels cytology, Body Patterning, Endothelial Cells enzymology, Phospholipase C gamma metabolism, Stem Cells cytology, Stem Cells enzymology, Vascular Endothelial Growth Factor Receptor-2 metabolism
- Abstract
Vascular endothelial growth factor receptor 2 (VEGFR2) plays crucial roles in vasculogenesis, a process involving cell proliferation, migration and differentiation. However, the molecular mechanism by which VEGFR2 signaling directs vascular endothelial differentiation of VEGFR2(+) mesodermal progenitors is not well understood. In this study, we examined the signal transduction pathway downstream of VEGFR2 for endothelial differentiation using an in vitro differentiation system of mouse embryonic stem-cell-derived VEGFR2(+) cells. Using chimeric receptors composed of VEGFR2 and VEGFR3, the third member of the VEGFR family, we found that signaling through tyrosine 1175 (Y1175, corresponding to mouse Y1173) of VEGFR2 is crucial for two processes of endothelial differentiation: endothelial specification of VEGFR2(+) progenitors, and subsequent survival of endothelial cells (ECs). Furthermore, we found that phospholipase Cgamma1 (PLCgamma1), which interacts with VEGFR2 through phosphorylated Y1175, is an inducer of endothelial specification. In contrast to VEGFR2, VEGFR3 does not transmit a signal for endothelial differentiation of VEGFR2(+) cells. We found that VEGFR3 does not activate PLCgamma1, although VEGFR3 has the ability to support endothelial cell survival. Taken together, these findings indicate that VEGFR2-PLCgamma1 signal relay gives rise to the unique function of VEGFR2, thus enabling endothelial differentiation from vascular progenitors.
- Published
- 2009
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36. Ras signaling directs endothelial specification of VEGFR2+ vascular progenitor cells.
- Author
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Kawasaki K, Watabe T, Sase H, Hirashima M, Koide H, Morishita Y, Yuki K, Sasaoka T, Suda T, Katsuki M, Miyazono K, and Miyazawa K
- Subjects
- Animals, Cell Differentiation drug effects, Embryo, Mammalian cytology, Embryonic Stem Cells cytology, Enzyme Inhibitors pharmacology, Methionine analogs & derivatives, Methionine pharmacology, Mice, Mice, Inbred C57BL, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors, Vascular Endothelial Growth Factor A metabolism, Endothelial Cells cytology, Proto-Oncogene Proteins p21(ras) metabolism, Signal Transduction, Vascular Endothelial Growth Factor Receptor-2 metabolism
- Abstract
Vascular endothelial growth factor receptor 2 (VEGFR2) transmits signals of crucial importance to vasculogenesis, including proliferation, migration, and differentiation of vascular progenitor cells. Embryonic stem cell-derived VEGFR2(+) mesodermal cells differentiate into mural lineage in the presence of platelet derived growth factor (PDGF)-BB or serum but into endothelial lineage in response to VEGF-A. We found that inhibition of H-Ras function by a farnesyltransferase inhibitor or a knockdown technique results in selective suppression of VEGF-A-induced endothelial specification. Experiments with ex vivo whole-embryo culture as well as analysis of H-ras(-/-) mice also supported this conclusion. Furthermore, expression of a constitutively active H-Ras[G12V] in VEGFR2(+) progenitor cells resulted in endothelial differentiation through the extracellular signal-related kinase (Erk) pathway. Both VEGF-A and PDGF-BB activated Ras in VEGFR2(+) progenitor cells 5 min after treatment. However, VEGF-A, but not PDGF-BB, activated Ras 6-9 h after treatment, preceding the induction of endothelial markers. VEGF-A thus activates temporally distinct Ras-Erk signaling to direct endothelial specification of VEGFR2(+) vascular progenitor cells.
- Published
- 2008
- Full Text
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37. Seasonal variation in the atmospheric deposition of inorganic constituents and canopy interactions in a Japanese cedar forest.
- Author
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Sase H, Takahashi A, Sato M, Kobayashi H, Nakata M, and Totsuka T
- Subjects
- Adsorption, Japan, Microscopy, Electron, Scanning, Nitrites analysis, Nitrogen analysis, Plant Leaves physiology, Plant Leaves ultrastructure, Plant Stems metabolism, Potassium analysis, Quaternary Ammonium Compounds analysis, Rain, Wettability, Wind, Air Pollutants analysis, Cryptomeria, Environmental Monitoring methods, Seasons, Trees
- Abstract
The seasonal changes in throughfall (TF) and stemflow (SF) chemistry and the canopy interactions of K+ and N compounds were studied in a Japanese cedar forest near the Sea of Japan. The fluxes of most ions, including non-sea-salt SO4(2-), from TF, SF, and rainfall showed distinct seasonal trends, increasing from autumn to winter, owing to the seasonal west wind, while the fluxes of NH4+ and K+ ions from TF+SF might have a large effect of canopy interactions. The contact angle (CA) of water droplets on leaves decreased with leaf aging, suggesting that surface wettability increases with leaf age. The K+ concentration in TF was negatively correlated with the CA of 1-year-old leaves, while the NH4+ concentration was positively correlated with the CA. The net fluxes of NH4+ and NO3(-) from TF were positively correlated with the CA. The increase in wettability may accelerate leaching of K+ or uptake of NH4+.
- Published
- 2008
- Full Text
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38. Bone bruise in magnetic resonance imaging strongly correlates with the production of joint effusion and with knee osteoarthritis.
- Author
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Oda H, Igarashi M, Sase H, Sase T, and Yamamoto S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Cohort Studies, Contusions complications, Contusions diagnostic imaging, Female, Humans, Hydrarthrosis diagnostic imaging, Hydrarthrosis pathology, Knee Injuries complications, Knee Injuries diagnostic imaging, Magnetic Resonance Imaging, Male, Middle Aged, Osteoarthritis, Knee diagnostic imaging, Osteoarthritis, Knee pathology, Radiography, Risk Factors, Severity of Illness Index, Contusions pathology, Hydrarthrosis etiology, Knee Injuries pathology, Leg Bones injuries, Osteoarthritis, Knee etiology
- Abstract
Background: The findings of magnetic resonance imaging (MRI) have not been studied systematically in patients with osteoarthritis (OA). The objective here was to compare MRI findings with radiological findings in patients with knee pain and to identify factors that influence the progression of OA of the knee., Methods: Of 212 patients with knee pain and MRI of the knee joint, 161 patients were selected for the study after exclusion of cases of trauma and other arthritides. MRI was used to evaluate the presence and degree of bone bruise, hydrarthrosis, and injuries to the cruciate ligament and meniscus. Bone bruise was classified into four types, and hydrarthrosis into four grades. Radiologically, OA progression in the femorotibial and patellofemoral joints was analyzed according to the Kellgren-Lawrence classification. Age was divided into four groups based on distribution quartiles. Logistic regression analysis and a generalized linear model with Poisson regression were used to analyze correlations among these factors., Results: Bone bruise was present in 87 cases, hydrarthrosis in 100, cruciate ligament injury in 20, and meniscus injury in 98. The presence of bone bruise was not related to age, cruciate ligament injury, meniscus injury, nor to OA of the patellofemoral joint, but was related to hydrarthrosis and to OA of the femorotibial joint. Femorotibial OA was much more strongly associated with bone bruise than with hydrarthrosis. Furthermore, analyzing the relation between the types of bone bruise and the degree of hydrarthrosis using a generalized linear model with Poisson regression, there was a positive correlation between the grade of bone bruise and the amount of hydrarthrosis., Conclusions: A factor associated with the degree of osteoarthritis of the knee is bone bruise observed on MRI. The degree of hydrarthrosis is related to the grade of bone bruise, but is not linked to the degree of osteoarthritis.
- Published
- 2008
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39. Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-beta signaling.
- Author
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Nagano Y, Mavrakis KJ, Lee KL, Fujii T, Koinuma D, Sase H, Yuki K, Isogaya K, Saitoh M, Imamura T, Episkopou V, Miyazono K, and Miyazawa K
- Subjects
- Animals, COS Cells, Chlorocebus aethiops, DNA-Binding Proteins genetics, Down-Regulation drug effects, Down-Regulation physiology, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins genetics, Mice, Protein Binding drug effects, Protein Binding physiology, Proto-Oncogene Proteins genetics, Signal Transduction drug effects, Smad7 Protein genetics, Smad7 Protein metabolism, Transcription, Genetic drug effects, Transcription, Genetic physiology, Transforming Growth Factor beta pharmacology, Ubiquitin genetics, Ubiquitin-Protein Ligases, DNA-Binding Proteins metabolism, Intracellular Signaling Peptides and Proteins metabolism, Proto-Oncogene Proteins metabolism, Signal Transduction physiology, Transforming Growth Factor beta metabolism, Ubiquitin metabolism
- Abstract
Transforming growth factor-beta (TGF-beta) signaling is controlled by a variety of regulators that target either signaling receptors or activated Smad complexes. Among the negative regulators, Smad7 antagonizes TGF-beta signaling mainly through targeting the signaling receptors, whereas SnoN and c-Ski repress signaling at the transcriptional level through inactivation of Smad complexes. We previously found that Arkadia is a positive regulator of TGF-beta signaling that induces ubiquitin-dependent degradation of Smad7 through its C-terminal RING domain. We report here that Arkadia induces degradation of SnoN and c-Ski in addition to Smad7. Arkadia interacts with SnoN and c-Ski in their free forms as well as in the forms bound to Smad proteins, and constitutively down-regulates levels of their expression. Arkadia thus appears to effectively enhance TGF-beta signaling through simultaneous down-regulation of two distinct types of negative regulators, Smad7 and SnoN/c-Ski, and may play an important role in determining the intensity of TGF-beta family signaling in target cells.
- Published
- 2007
- Full Text
- View/download PDF
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