Search

IC50 values for the inhibition of 93 human kinases by E7090.

Western blot analysis of FGFR1 in human lung cancer cell lines harboring FGFR1 amplifications.

The FGFR signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR. Furthermore, E7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. Our results suggest that E7090 is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. It is currently being investigated in a phase I clinical trial. Mol Cancer Ther; 15(11); 2630–9. ©2016 AACR.

Supplementary Table legends and Supplementary Figure legends.

Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex natural products.

Background and objectives: Natural products have been a rich source of inspiration for drug discovery as demonstrated by the fact that over one-third of current therapeutic agents are natural products or compounds derived from them. Particularly, when the supply of a natural product from the natural source is limited, organic synthesis can offer a solution. However, with increasing structural complexity, this approach becomes exponentially more challenging, as a synthesis must meet various requirements, including high overall efficiency, scalability, cost-effectiveness, and product purity as well as conforming to good manufacturing practice (GMP) regulations. Despite the outstanding in vivo antitumor activity in mice, the limited supply from the natural sources has prevented drug development based on intact halichondrins. Methods: We successfully synthesized 19.5 g of C52-halichondrin-B alcohol with 99.84% purity via a total synthesis. From 15.0 g of this material, we obtained 11.5 g of C52-halichondrin-B amine (E7130) with 99.81% purity under GMP conditions. With totally synthetic E7130, a novel microtubule dynamics inhibitor, we studied the activities in both of in vitro and in vivo. The inhibitory activity of E7130 towards tubulin polymerization was analyzed in the cell-free system in which tubulin polymerization could be monitored by fluorescence enhancement due to the incorporation of a fluorescence reporter into the microtubules during polymerization. We analyzed in vivo antitumor activities using both a human cancer cell line orthotopic transplantation mouse model and subcutaneous xenograft models. The immunohistochemical analyses were performed with tumor tissues collected from mouse models to analyze histological changes after treatment with E7130. Results: E7130 is a novel microtubule dynamics inhibitor with exceedingly potent in vitro and in vivo anticancer activities. Significantly, E7130 not only is cytotoxic, but can also increase CD31-positive endothelial cells in tumors and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. Notably, this dual activity has been recognized for the first time through this study. According to these unique tumor microenvironment ameliorative effects, E7130 can augment the effect of other antitumor treatments in mouse models. In particular, a dose of 90 µg/kg, one-half of the maximum tolerated dose in mice, showed a prominent combinational effect with cetuximab, which suggests that E7130 has a different mechanism than other microtubule-targeted drugs. Conclusions: E7130 ameliorates the tumor microenvironment to improve cancer treatment when used in combination with other compounds. The data provide compelling evidence that E7130 is a promising molecular-targeting anticancer agent. Citation Format: Satoshi Kawano, Takanori Abe, Ken Ito, Kenzo Yahata, Kazunobu Kira, Tsuyoshi Akagi, Makoto Asano, Kentaro Iso, Yuki Sato, Fumiyoshi Matsuura, Isao Ohashi, Yasunobu Matsumoto, Minetaka Isomura, Takeo Sasaki, Takashi Fukuyama, Yusuke Miyashita, Yosuke Kaburagi, Akira Yokoi, Osamu Asano, Takashi Owa, Yoshito Kishi. E7130 derived from total synthesis of halichondrin as a novel tumor-microenvironment ameliorator [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4179.

Background and objectives: Despite the outstanding antitumor activity of halichondrins in mice, the limited supply from the natural sources has prevented drug development using intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) under good manufacturing practice (GMP) conditions. E7130 is not only a novel microtubule dynamics inhibitor, but also a novel tumor-microenvironment ameliorator. E7130 can increase intratumoral CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts (CAFs) at pharmacologically relevant compound concentrations. Here, we analyzed the molecular mechanisms of the α-SMA-positive CAF reduction with E7130. Methods: The expression levels of α-SMA, ECM proteins, ER-TR7 (pan-fibroblast marker), and Ki67 were examined using E7130-treated tumors. In vitro co-culture experiments, normal human fibroblasts were co-cultured with human cancer cells. To examine the effects of E7130 on the TGF-β-induced CAF activation, normal human fibroblasts were treated with TGF-β (final concentration of 1 ng/mL) and E7130 at the several concentrations, and gene expression analysis and immunocytochemical analysis were conducted. Results: E7130 reduced α-SMA-positive CAF and malignant ECM proteins without changing total fibroblast number in tumors. The in vitro co-culture system revealed that TGF-β from cancer cells activate normal human fibroblast and increased α-SMA expression. In addition, treatment with E7130 interfered with α-SMA induction by TGF-β in fibroblasts without growth inhibitory activity. We further found that E7130 inhibited TGF-β-induced PI3K/AKT/mTOR pathway, which resulted in the reduction of α-SMA expression in fibroblasts. Moreover, TGF-β treatment enhanced β-tubulin expression and focal adhesions formation, which were diminished by co-treatment with E7130 in fibroblasts. Many signaling complexes are assembled in focal adhesion sites, and those complexes dispatch several downstream signals, including those involved in the PI3K/AKT/mTOR pathway. Conclusions: Drug discovery using halichondrins was based on their outstanding in vivo antitumor (inhibitory) activity in mice and bone metastasis in mouse melanoma model first reported in 1996. From these results, we hypothesized that halichondrins are not simple microtubule-targeted compounds in tumor cell, and have developed E7130, which harbors unique tumor microenvironment ameliorating effects. Here we proved that E7130 impedes the TGF-β-induced myofibroblast transdifferentiation process without killing the fibroblast by disrupting microtubule network formation, which is important for focal adhesion assembly and thereby the downstream activation of the PI3K/AKT/mTOR pathway. Citation Format: Takanori Abe, Satoshi Kawano, Ken Ito, Kenzo Yahata, Kazunobu Kira, Tsuyoshi Akagi, Makoto Asano, Kentaro Iso, Yuki Sato, Fumiyoshi Matsuura, Isao Ohashi, Yasunobu Matsumoto, Minetaka Isomura, Takeo Sasaki, Takashi Fukuyama, Yusuke Miyashita, Yosuke Kaburagi, Akira Yokoi, Osamu Asano, Takashi Owa, Yoshito Kishi. Mechanism of action analysis of anti-CAF activity of E7130, a novel tumor-microenvironment ameliorator [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4183.

Humans and dogs are the two major hosts of Strongyloides stercoralis, an intestinal parasitic nematode. To better understand the phylogenetic relationships among S. stercoralis isolates infecting humans and dogs and to assess the zoonotic potential of this parasite, we analyzed mitochondrial Cox1, nuclear 18S rDNA, 28S rDNA, and a major sperm protein domain-containing protein genes. Overall, our analyses indicated the presence of two distinct lineages of S. stercoralis (referred to as type A and type B). While type A parasites were isolated both from humans and dogs in different countries, type B parasites were found exclusively in dogs, indicating that the type B has not adapted to infect humans. These epidemiological data, together with the close phylogenetic relationship of S. stercoralis with S. procyonis, a Strongyloides parasite of raccoons, possibly indicates that S. stercoralis originally evolved as a canid parasite, and later spread into humans. The inability to infect humans might be an ancestral character of this species and the type B might be surmised to be an origin population from which human-infecting strains are derived.

The FGFR signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR. Furthermore, E7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. Our results suggest that E7090 is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. It is currently being investigated in a phase I clinical trial. Mol Cancer Ther; 15(11); 2630–9. ©2016 AACR.

Our previous study showed that algorithms using quantified aerial perspective can control the subjective depth of stereoscopic images. With the superposition of spatial frequencies, the naturalness of processed images can be improved. In this paper, details of the algorithms and the results of a subjective assessment are presented and discussed.

Our previous study showed that the algorithm using quantified aerial perspective could control subjective depth in stereoscopic still pictures. Being integrated with a motion-estimation technique, this algorithm can be applied to motion pictures. In this paper, details of the algorithm and results of subjective assessment will be presented and discussed.

Using a unique new cross-national survey of Japanese and Korean workers, we report the first systematic evidence on the effects on employee voice of High Performance Work Practices (HPWPs) from the two economies which are noted for the wide use of HPWPs. We find for both nations that: (i) workers in firms with HPWPs aimed at creating opportunities for employees to get involved (such as shopfloor committees and small group activities) are indeed more likely to have stronger senses of influence and voice on shopfloor decision making than other workers; (ii) workers whose pay is tied to firm performance are more likely to have a stake in firm performance and hence demand such influence and voice; and (iii) consequently workers in firms with HPWPs are more likely to make frequent suggestions for productivity increase and quality improvement. As such, this paper contributes to a small yet growing new empirical literature which tries to understand the actual process and mechanism through which HPWPs lead to better enterprise performance.

I analyse, theoretically and empirically, the effects of pension benefits, family conditions and the personal characteristics of older individuals on their labour supply, wages, hours worked and job satisfaction, in the framework of the Nash bargaining condition whereby an older worker and a firm bargain over employment conditions such as wages, hours of work and job investment. It is stressed that as workers become older they tend to give greater priority to the number of hours worked, work environment and type of job than to wages, and try to improve these through job investment, even at the cost of lower wages.

目的および対象:当院で過去10年間に行われた唾液腺穿刺吸引細胞診453例 (511検体) 中, 組織診断が明らかな249例を対象とし, 唾液腺穿刺吸引細胞診の成績をまとめ, 若干の知見を得たので報告する.成績:唾液腺穿刺吸引細胞診の正診率は96.2%, 特異性98.6%, 感度72.7%, 細胞採取不良による判定不能例は13例であった. 誤陽性は3例で, 多形腺腫を腺様嚢胞癌および腺房細胞癌, 基底細胞腺腫を粘表皮癌と誤判定した.誤陰性は6例で, 悪性リンパ腫と診断しえなかった3例と多形腺腫内癌を多形腺腫, 粘表皮癌を多形腺腫, 腺房細胞癌をワルチン腫瘍とした各1例であった.結論:唾液腺穿刺吸引細胞診は治療指針の決定や術前検査として非常に有用とされており, 唾液腺穿刺吸引細胞診の精度の向上にさらに努めていく必要がある. また, 唾液腺悪性リンパ腫は, 組織学的にも反応性と腫瘍性の鑑別困難な症例が多く, 細胞診では確定診断しがたいと思われる. 今後, 細胞診材料でも, 形態学的診断に加え, 免疫染色やpolymerase chain reaction (PCR) 法などの分子生物学的手法を取り入れた総合的な診断が必要と考えられた.

背景: 標本枚数に限りがある細胞診検査において, 細胞転写法を用いることにより多種の染色法が可能となる. 今回, 細胞転写法が有用であった気管支アミロイドーシスの1例を報告する.症例: 81歳男性, 血疾, 喘鳴を主訴とし胸部X線写真上肺癌が疑われ入院となった. 気管支鏡検査で発赤を伴う隆起性の粘膜病変が広範に認められ, 擦過細胞診では壊死様無構造物質, 炎症細胞, 組織球がみられたが異型細胞, 悪性細胞は認められなかった. 壊死様無構造物質には通常壊死物質にみられる壊死細胞の核など細胞残存所見がなく, アミロイドーシスを疑った. しかし, 患者の一般状態不良により生検が行えず, 確定診断のため, 壊死様無構造物質について細胞転写法を用い検討した. その物質は, コンゴレッド染色陽性, 抗アミロイドP-component抗体陽性, 電子顕微鏡的検索で幅約10nm前後のアミロイド線維が認められ, 細胞診材料のみでアミロイドーシスと確定しえた.結論: 細胞転写法は, 細胞診検査においてきわめて有用性の高い方法で, 今後多くの症例に応用できると思われた.

Jaw jerk was evoked in 12 normal subjects (N group) and 12 patients with unilateral craniofacial pain who had neither mandibular deviation nor organic changes in the temporomandibular joint (P group), about every ca. 2 sec by tapping the center of the chin with a reflex hammer, in which a microswitch was embedded to indicate the time of its contact with the chin. The surface electromyogram of the masseter muscle was recorded bilaterally. It was found that (1) in the N group, there was no difference in the onset latency between the right (6.30 +/- 1.06 ms; n = 192) and left (6.32 +/- 1.04 ms; n = 192) sides (P > 0.05); (2) in the P group, the latency was shorter on the painful side than on the pain-free side; and (3) after pain was relieved by treatment, the bilateral difference in the latency of jaw jerk disappeared, and the latencies fell to that in normal subjects. It was concluded that the bilateral difference of the latency of jaw jerk can be used as an investigative criterion for the existence of pain.

A cytogenetic study of a 38-year-old patient with acute lymphoblastic leukemia (ALL) revealed a t(1;19)(q23;pl3), which is a characteristic translocation of childhood ALL. The leukemic cells were positive for the CD10, CD19, HLA-DR, TdT and cytoplasmic μ-chain. Both of the immunoglobulin heavy chain gene loci were rearranged and the RNA-based polymerase chain reaction demonstrated the E2A/PBX1 fusion transcript which is the result of the t(1;19). This finding suggests that the t(l;19) is implicated not only in childhood ALL but also in adult ALL patients.(Internal Medicine 32: 584-587, 1993)

To apply an irradiation technique to sterilize “Hybrid” biomedical materials including enzymes, we selected papain, a well-characterized plant endopeptidase as a model to examine durability of enzyme activity under the practical irradiation condition in which limited data were available for irradiation inactivation of enzymes. Dry powder and frozen aqueous solution of papain showed significant durability against 60 Co-gamma irradiation suggesting that, the commercial irradiation sterilizing method is applicable without modification. Although irradiation of unfrozen aqueous papain solution showed an unusual change of the enzymatic activity with the increasing doses, and was totally inactivated at 15 kGy, we managed to keep the residual activity more than 50% of initial activity after 30-kGy irradiation, taking such optimum conditions as increasing enzyme concentration from 10 to 100 mg/ml and purging with N 2 gas to suppress the formation of free radicals.

Formation of an epoxide before 9-membered ring cyclization and SmI2 mediated reductive olefination in the presence of the epoxide successfully produced the epoxybicyclo[7.3.0]dodecadienediyne core of the kedarcidinchromophore.

Formation of an epoxide before 9-membered ring cyclization and SmI2 mediated reductive olefination in the presence of the epoxide successfully produced the epoxybicyclo[7.3.0]dodecadienediyne core of the kedarcidin chromophore.

The ageing of a country’s population has a variety of effects on its society and economy. Of most serious concern is the impact on public finances for pensions and medical care. But ageing not only increases the burden on the younger generation, it also depletes the resources necessary to drive strong economic growth. In this respect, Japan is confronted with a difficult situation.1 As an illustration, it would be worthwhile to point out that, as of 2004, the percentage of the total population that was 60 years old or over was 19.5%, the highest in the world, while the total fertility rate was 1.29, close to the lowest in the world. Furthermore, the situation is rapidly becoming more serious.

In advanced studies directed toward the total synthesis of the kedarcidin chromophore, we have successfully achieved the late-stage installation of the nine-membered diyne ring in the presence of the highly functionalised ansamacrocyclic bridge.

The fibroblast growth factor (FGF) signaling pathway comprises 18 ligands and 4 FGF receptor subtypes, FGFR1, 2, 3 and 4, which are known as receptor-type tyrosine kinases corresponding to those ligands. Upon ligand binding, FGFRs activate an array of downstream signaling pathways, such as the mitogen activated protein kinase (MAPK) and the phosphoinositide-3-kinase (PI3K)/Akt pathways. Genetic abnormalities (gene fusion, mutation and amplification) of FGFRs are known to cause constitutive activation of their signaling pathways, which play an important role in proliferation, survival and migration of cancer cells, tumor angiogenesis, drug resistance, etc. These abnormalities have also been reported to be involved in different cancer types including lung, breast, endometrial, gastric, and bladder cancer so far. Therefore, FGFRs are considered as one of potential targets for cancer therapy. E7090 is an orally available, selective and potent inhibitor of FGFR1, 2 and 3 tyrosine kinase activities. E7090 displayed inhibition of FGFR1, 2, and 3 kinase activities with the IC50 values of approximately 1 nmol/L. E7090 also inhibited the growth of SNU-16, human gastric cancer cell line harboring FGFR2 amplification with an IC50 value of 3 nmol/L. This activity was about 60-fold stronger than that against VEGF-stimulated HUVEC growth. Kinase profiling assay consisting of 93 kinases including non-receptor and serine/threonine kinases, also demonstrated that E7090 inhibited limited kinases including FGFR-1, -2 and -3. In addition, E7090 inhibited proliferation of human cancer cell lines harboring various types of FGFRs gene abnormalities such as amplification, mutation, or translocation in vitro, which are confirmed by the inhibition of FGFR signaling. E7090 also showed significant antitumor activities on various human xenografts harboring FGFRs gene abnormalities in a dose dependent manner and demonstrated tumor shrinkage at several doses in some models. Furthermore, pharmacodynamics analysis revealed that E7090 inhibited phosphorylation of FGFRs in SNU-16 xenograft tumors in a dose-dependent manner. Overall, the in vitro and in vivo studies confirm that E7090 is a potent and selective FGFRs inhibitor, showing promising antitumor activities with wider therapeutic windows in preclinical cancer models harboring FGFRs gene abnormalities. E7090 has been advanced through preclinical development and we disclose here the first details of its preclinical profile. Citation Format: Saori Watanabe Miyano, Yuji Yamamoto, Kotaro Kodama, Setsuo Funasaka, Satoshi Nagao, Naoko Hata Sugi, Hiroko Kuramochi, Katsuyuki Ishikawa, Kiyoshi Okamoto, Yukinori Minoshima, Takayuki Nakagawa, Yusuke Nakatani, Yuki Karoji, Isao Ohashi, Yoshinobu Yamane, Keigo Tanaka, Toshimi Okada, Tomohiro Matsushima, Junji Matsui, Masao Iwata, Akihiko Tsuruoka, Toshimitsu Uenaka. E7090: A potent and selective FGFR inhibitor with activity in multiple FGFR-driven cancer models with distinct mechanisms of activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 770. doi:10.1158/1538-7445.AM2015-770

A 98-year-old woman was admitted to our hospital complaining of anorexia, epigastralgia, and vomiting. An elastic hard tumor was palpable in her epigastric region. CT and US examination revealed a huge cystic lesion adjacent to the left lobe of the liver and the stomach. Her serum levels of CEA (13.6 ng/ml), CA19-9 (95 U/ml) and CA125 (99 U/ml) were high. She suffered from aspiration pneumonia on the 10th day of admission, which progressed to acute respiratory distress syndrome. On the 20th day of admission, the epigastric tumor suddenly disappeared. She passed away on the 31st day due to respiratory failure. Autopsy revealed that she had a ruptured pancreatic anaplastic mucinous cystadenocarcinoma. To the best of our knowledge, this is the oldest reported case of ruptured pancreatic cystadenocarcinoma in the world.

[Structure: see text] The streamlined assembly of the ansamacrolide framework of the kedarcidin chromophore via an efficient atropselective Sonogashira coupling step is described. To this end, two newly improved practical syntheses of the cyclopentene and diyne fragments have been developed, which feature 0.2 mol % catalytic loadings for an RCM step and i-PrMgCl/CH2I2 as a new entry to gem-disubstituted epoxides from ketones, both being applicable to 49-g scales.

This paper analyzes the effects of pension benefits, family conditions, and personal characteristics of the elderly on their labor supply, wages, hours of work and job satisfaction in the framework of the Nash bargaining that an old worker and a firm bargain over employment conditions such as wages, hours of work and job investment. It will be stressed that as workers become aged, they come to put more priority on hours of work, work circumstances, the contents of a job rather than wages, and make them improved by job investment in the form of lower wages. This paper also shows empirically, controlling the income effect of pensions, that the effects of the reduction scheme of the Employees' Pension Plan on hours worked and labor participation of the elderly had disappeared by 2000.

Using a unique new survey, the Japanese Worker Representation and Participation Survey (JWRPS), this paper presents the first evidence on the representation/participation gaps among Japanese workers and its links to the degree of their discontent with work and the efficacy of celebrated participatory employment practices. We find that: (i) contrary to the popular rhetoric of the end of "participatory Japanese management", Japanese workers still desire more involvement and greater voice in firm decisions; and (ii) in spite of their strong desire to have more influence, many Japanese workers consider their current level of say at work less than adequate, resulting in significant representation/participation gaps which are comparable to what has been found for U.S. workers. Furthermore, we find an alarming degree of discontent with work among Japanese workers, measured by diverse variables, and weak employee involvement and influence are found to be significantly linked to the degree of such discontent. Finally, our analysis of the survey data yields evidence in support of the hypotheses that: (i) working in firms with strong participatory programs will significantly enhance employee voice; (ii) among those working in participatory firms, actually participating in these programs will yield an additional boost for employee voice; and (iii) financial participation schemes will align the interest of employees with the interest of the firm and thus make employees wanting to have more influence in firm decisions. Our findings suggest that weakening participatory employment practices (as the popular rhetoric at times suggests) may result in exacerbating the already alarming degree of employee dissatisfaction in Japan.

This paper analyzes the effects of inter-industry and firm size on wage differentials,focusing on how their estimated effects vary by the introduction of elements indicating firm characteristics such as wage-experience profiles.Using the worker-establishment matched data, we find that inter-industry effects are larger than firm size ones judging from their explanatory powers and the wage distributions caused by them although the introduction of firm characteristics reduces more the effect of industry. Since this paper is based on the efficiency wage hypothesis to explain wage differentials, it is required to test for the bonding critique. Checking how steeper wage profiles affect wages of young workers, we find that even those who work at firms where wage profiles are steeply rising are not paid lower. This result supports the efficiency wage hypothesis to be a good explanation for wage differentials.

In the alpha-glycosylation study of the unusual, 2-deoxy amino sugar of kedarcidin, polystyrene-supported DBU (PDBU) was found to be invaluable to the clean preparation of the highly labile Schmidt donor of l-kedarosamine. By further recognition that the C4-alcohol should be left free for favorable acceptor reactivity, we could for the first time successfully assemble the C13-O-alpha-glycoside of the ansamacrolide substructure of the kedarcidin chromophore. [reaction: see text]

Since the work of Abegglen (1958), many authors, both Japanese and Western, have characterised Japanese industrial relations by seniority provisions, permanent employment and enterprise unionism. These so-called characteristics have attracted the attention of many foreign scholars as providing an explanation for Japan’s high productivity of labour and good economic performance. It is, however, a matter of debate how Japanese industrial relations could work effectively in bringing them about. Economists’ standpoints on this controversy depend critically on the way they interpret Japanese industrial relations. This chapter will attempt to provide an explanation of how the Japanese employment system functions to promote workers’ incentives, focusing on intra-firm transfers.

Until now two reasons have been advanced to explain Japan’s good economic performance — high productivity, low unemployment and steady rates of economic growth. One focuses on Japanese industrial relations which have been characterized by seniority-based wages, permanent employment and enterprise unionism, and the other attaches great importance to the labour compensation system relatively unique to Japan, that is, the bonus payment system. However, it is still a matter of some dispute quite how these features contribute to good economic performance in Japan.

— This paper considers the architecture and the effectiveness of new algorithms that control the subjective depth on 3-D displays by modulating the contrast of stereoscopic pictures on the basis of a quantified monocular depth cue. First, a psychophysical experiment to quantify the relationship between contrast and subjective depth was conducted. This experimental result shows that the higher the contrast, the nearer the object will be perceived, corresponding to the qualitative relationship. Second, this result was applied to image-processing algorithms that expand or contract the subjective depth of stereoscopic pictures. Subjective assessments to verify the effectiveness of the algorithms were also conducted. The results suggest that the algorithms will allow viewers to experience a highly realistic sensation.

This paper attempts to reformulate in a general-equilibrium framework M. W. Reder's model, which explains cyclical variations in wage differentials and their general tendencies to narrow. Specifically, the author focuses on the three aspects of his model: the microeconomic behavior of a firm under imperfect information about labor quality; the mechanism of the economy creating unemployment; and the interaction between wage differentials and unemployment. Its implications for the macroeconomic issues on the characteristics of current unemployment and the question of why aggregate employment fluctuates are also explored. Copyright 1987 by University of Chicago Press.

(Object) There are many reports on the fibrinolytic dynamics in blood as to the development of peptic ulcers. However, these studies have not been completed and we have many problems to be solved on this subject. In the present study we reexamined the correlation between the fibrinolysis and activity of the coagulation system.(Method) Ulcers were induced by contact freezing of the left gastric artery on the gastric serosa in Mongorel dogs for materials. The basis of ulcers was confined within the limit of the submucosal layer in all cases and fibrin deposit blood vessels were maintained comparatively intact. The plasminogen activator was observed at necrotic portions, but activity was determined at the margin, peripheral elevation and distal mucosa of ulcers and the plasminogen and plasmin inhibitors in the circulating blood were analyzed by affinity chromatography at the same time. The tissue was observed by antifibrinous staining.(Result) At the margin of ulcer: Free plasminogen activator was proved at the local peripheral circulatory insufficiency but it was diministred after this maniplation. In the peripheral elevation of ulcer: Free activator was detected when circulatory insufficiency was invited and a secondary liberation of the activator due to the elevation of membrane permeability of peripheral cells containing quinines was observed. In the distal mucosa: The same correlation as in the peripheral elevation was noticed, but the secondary liberation of activator showed considerably wide variation. The activity of plasminogen or plasmin inhibitors was correlated with that of plasminogen activator in blood. The coagulation system had an inhibitory action on factors V and VIII, but it was correlated with neither PT nor PTT.(Conclusion) The activity of plasminogen activator in the initial lesions of acute peptic ulcers showed clear biphasic peaks and was well correlated with that of plasmin inhibitor or of the coagulation system at the same time.

The profit-sharing model has attracted considerable attention as a hypothesis to explain wage flexibility and employment stability in Japan. This paper presents an alternative explanation of how bonuses and basic wages are determined in Japan, based on the efficiency wage hypothesis. In particular, we focus on the aspect that bonuses are paid to compensate employees for the intensity of work experienced during the last period, and basic wages are affected mainly by labor market conditions and are not firm-specific. We compare the two models, testing them for both industry aggregate data and firm microdata.

A new technique for factor XIII determination, spot fluorescent method (K. Aizawa et al., SEIKAGAKU, vol. 46, 568, 1974, abstract) effectively used screening many test samples in normal, in arteriosclerotic patients, and in pregnant women. The results were summarized as followings.1) Plasma factor XIII concentration in normal persons is gradually increased depending on age from teenage to older, and rapidly increased from late middle age. There is obvious positive relationship between plasma factor XIII and age.2) The avarage and the standard deviation in young adult was 18.4±3.03) There was little relationship between factor XIII and puls wave velocity which was considered to indicate the extent of aortic sclerosis. But factor XIII in the persons who gave myocardial disorders i. e. abnormal ST, T in the ECG were meaningfully high, while the broad distribution from low to high was seen in the patient group of angina on the other hand.4) Every malignant tumor and liver cirrhosis showed abnormally low level of plasma factor XIII.5) Fibrinogen, platelet count, and total protein were all once decreased by pregnancy, and became recovered from 1st trimester, 2nd trimefter, or 3rd trimester stage individually.On the other hand factor XIII was increased by pregnancy and maintained in the high level during all trimester, and rapidly decreased after delivery.