Transforming growth factor(TGF)pl is a potent inhibitor of growth in mouse osteoblastic MC3T3-El cells. To isolate genes that are induced by TGFPl, the differential screening method was adopted using a cDNA library constructed from cells treated with TGFPl for 4 h. Six independent cDNA clones were isolated (TGFP-stimulated clone, TSC-5, TSC-36, TSC-115, TSC-128, TSC-160 and TSC-161), the expression of which was increased by TGFPl-treatment with maximal expression at 6-10 h. The steady-state levels of TSC-36, TSC-128 and TSC-160 increased almost tenfold, whereas those of TSC-5, TSC-115 and TSC-161 were elevated at most threefold. From partial nucleotide sequences, TSC-160 was found to be identical to rrg (rus-recision gene, lysyl oxydase), and TSC-115 had 80% similarity with tropomyosin cDNA, whereas other genes seemed novel. Expression of TSC-36 and TSC-160 was dramatically decreased in v-Ki-ras-transformed MC3T3 cells or in transformed NIH 3T3 cells (DT), and was recovered to normal levels in a flat revcrtant (C11). A nearly full-length copy of TSC-36 cDNA was isolated, and an open reading frame indicated that it encodes a protein of 35 kDa. An antiserum was raised against the C-terminal peptide predicted from the nucleotide sequence, and a polypeptide with an approximate molecular mass of 38 kDa was detected in cultured medium of MC3T3-El cells. The amino acid sequence of TSC-36 protein was found to have some similarity with follistatin, an activin-binding protein, and a limited similarity with the secreted protein rich in cysteine (SPARC).Growth of cells is controlled both positively and negatively by various autocrine, paracrine or endocrine growth factors, and both control mechanims are essential to maintain homeostasis. Transforming growth factor 81 (TGFp1) is a potent inhibitor of growth in various types of cells, and it also affects differentiation and gene expression [l -41. Growth of some types of mesenchymal cells is stimulated by TGFP1, but we previously reported that it inhibited growth of mouse osteoblastic cells (MC3T3-El) in the late G1 phase [ 5 ] . Growth inhibition is accompanied by induction of a certain kind of genes.TGFPl has a pronounced effect on expression of many cellular gencs, with the most striking effects on extracellularmatrix-related proteins. It increases expression of genes encoding extracellular matrix proteins [6-121 as well as proteCorrespondence to K. Nose,

S-1, a new oral antitumor agent, is composed of 1-(2-tetrahydrofuryl)-5-fluorouracil (Tegafur, FT), 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. FT which is a masked compound of 5-fluorouracil (5-FU) acts as an effector, while both CDHP and Oxo which do not have antitumor activity themselves act as modulators. In this study, the antitumor activity and intestinal toxicity of S-1 were investigated using experimental tumor models in rats, and compared with those of other oral fluoropyrimidines, namely 5-FU, FT, FCD (1 M FT/0.4 M CDHP) and UFT (combination of FT and uracil). In rats bearing subcutaneous Yoshida sarcoma, S-1 inhibited tumor growth at the lowest dose (ED50 value: S-1 5, UFT 22, FT 82, FCD 5, and 5-FU 19 mg/kg per day), and induced the least host body weight suppression, leading to the highest therapeutic index (TI) (S-1 4.5, UFT 1.4, FT 1.8, FCD 2.0, and 5-FU 1.4). S-1 also showed a higher therapeutic effect than UFT against AH-130 and Sato lung carcinoma. After administration of S-1 and UFT at equitoxic doses, S-1 showed a higher and more prolonged concentration of 5-FU than UFT both in plasma (AUC0-infinity: S-1 28 nmolh/ml, UFT 15 nmol.h/ml) and in tumor tissue (AUC0-infinity: S-1 95 nmolh/g tissue, UFT 52 nmolh/g tissue), leading to a higher 5-FU level incorporated into the RNA fraction (F-RNA level) in tumor tissue (AUC0-24: S-1 7.0 nmolh/mg RNA, UFT 4.3 nmolh/mg RNA) and 5-8% higher thymidylate synthase (TS) inhibition in tumor tissue at every time-point through 24 h. Compared with other oral fluoropyrimidines after administration of the maximal tolerable dose (MTD), S-1 caused the lowest rates of intestinal toxicities, such as diarrhea and occult blood in feces. S-1 also showed a higher antitumor effect on Yoshida sarcoma implanted intracolonically than UFT at an equitoxic dose (tumor weight: S-1 64 +/- 30 mg, UFT 133 +/- 52 mg; P < 0.05). These results suggest that CDHP, which is a potent inhibitor of 5-FU degradation, increases the antitumor activity of FT, and that Oxo, which is an inhibitor of 5-FU phosphorylation, locally protects the gastrointestinal tract from 5-FU-induced toxicity without decreasing the antitumor activity.

An innovative vibration-control system is proposed to reduce the dynamic response of tall buildings to wind and seismic loads. This system takes advantage of the so-called megasubstructure configuration, which is especially popular in tall buildings. Substructures contained in the megastructure serve as energy absorbers so that no additional mass is required for the intended vibration control as seen in the conventional mass damper systems. The proposed system naturally resolves the difficulties in augmenting damping capacities of tall buildings associated with the high rigidity and deformation in the dominant bending mode. Dynamic characteristics of the proposed control system including the frequency response and the energy flow are investigated. Optimal values of structural parameters such as the damping ratio and stiffness of the substructure are determined. The feasibility and effectiveness of this unique control system in improving human comfort and protecting structures under both wind and earthquake loads are demonstrated through analytical and numerical analysis.

BACKGROUND The purpose of the current study was to determine the maximum tolerated dose, dose‐limiting toxicities, pharmacokinetic profile, and recommended Phase II dose of oral administration of TAS‐102, a novel nucleoside formed by the combination of α,α,α‐trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI: 5‐chloro‐6‐(2‐iminopyrrolidin‐1‐yl)methyl‐2,4(1H,3H)‐pyrimidinedione). METHODS Eligible patients had advanced solid tumors, adequate organ function, and had not received anticancer therapy in the preceding 4 weeks. TAS‐102 was administered orally once daily for 14 days, followed by a 1‐week rest, repeated every 3 weeks. The initial dose of TAS‐102 administered was 100 mg/m2/day. The first 2 patients treated at that dose experienced substantial toxicity and, therefore, lower dose levels of TAS‐102 were subsequently explored. RESULTS Fourteen patients were enrolled; all patients were evaluable for toxicity assessment and 12 were evaluable for response. The initial dose explored was 100 mg/m2/day, based on a preclinical monkey model. However, the first 2 patients experienced bone marrow suppression of Grade 3 or 4 in course 1. The protocol was amended to study the next cohort of patients at 50 mg/m2/day. At this dose level no Grade 3 or 4 toxicities were observed in course 1. In the subsequent dose level (60 mg/m2/day), 3 of 6 patients experienced Grade 3 or 4 granulocytopenia as dose‐limiting toxicity. Three additional patients for a total of 6 were enrolled at 50 mg/m2/day without occurrence of dose‐limiting toxicity. Thus, 50 mg/m2/day was declared the maximum tolerated dose for this schedule. CONCLUSIONS The authors' study showed that 50 mg/m2/day was a tolerable dose of the novel antimetabolite FTD in combination with an inhibitor of its inactivating enzyme TP, and this is the recommended Phase II dose. Evaluation of this daily dose in malignancies for which fluoropyrimidines have failed is needed. Cancer 2006. © 2006 American Cancer Society.

We propose a substructure approach that allows for the local damage detection of a shear structure. This method requires only three sensors to identify localized damage in any story of a shear structure building. A substructure approach was used in this method to divide a complete structure into several substructures in order to significantly reduce the number of unknown parameters for each substructure so that damage detection processes can be independently conducted on each substructure. Thus, our method is suitable for use in a parallel and distributed damage detection system. Simulations and experiments on five-story buildings were conducted to test the feasibility of our proposed method.