パノビノスタットとプロテアソーム阻害薬は骨髄腫細胞の増殖と生存に必須の転写因子Sp1を相乗的に標的にする

Panobinostat, a pan-deacetylase inhibitor, synergistically elicits cytotoxic activity against myeloma (MM) cells in combination with the proteasome inhibitor bortezomib. Because precise mechanisms for panobinostat’s anti-MM action still remain elusive, we aimed to clarify the mechanisms of anti-MM effects of panobinostat and its synergism with proteasome inhibitors. Although the transcription factor Sp1 was overexpressed in MM cells, the Sp1 inhibitor terameprocol induced MM cell death in parallel with reduction of IRF4 and cMyc. Panobinostat induced activation of caspase-8, which was inversely correlated with reduction of Sp1 protein levels in MM cells. The panobinostat-mediated effects were further potentiated to effectively induce MM cell death in combination with bortezomib or carfilzomib even at suboptimal concentrations as a single agent. Addition of the caspase-8 inhibitor z-IETD-FMK abolished the Sp1 reduction not only by panobinostat alone but also by its combination with bortezomib, suggesting caspase-8-mediated Sp1 degradation. The synergistic Sp1 reduction markedly suppressed Sp1-driven prosurvival factors, IRF4 and cMyc. Besides, the combinatory treatment reduced HDAC1, another Sp1 target, in MM cells, which may potentiate HDAC inhibition. Collectively, caspase-8-mediated post-translational Sp1 degradation appears to be among major mechanisms for synergistic anti-MM effects of panobinostat and proteasome inhibitors in combination

MODULATION OF TRAIL ACTION BY TAK1 INHIBITION

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) agonists induce tumor-specific apoptosis indicating that they may be an attractive therapeutic strategy against cancers, including multiple myeloma (MM). Osteoclastogenesis is highly induced in MM, which in turn enhances MM growth, thereby forming a vicious cycle between MM tumor expansion and bone destruction. However, the effects of TRAIL on MM-enhanced osteoclastogenesis remain largely unknown. Here, we show that TRAIL induced apoptosis in MM cells, but not in osteoclasts (OCs), and that it rather facilitated receptor activator of NF-kB ligand–induced osteoclastogenesis along with upregulation of cellular FLICE inhibitory protein (c-FLIP). TRAIL did not induce death-inducing signaling complex formation in OCs, but formed secondary complex (complex II) with the phosphorylation of transforming growth factor b–activated kinase-1 (TAK1), and thus activated NF-kB signaling. c-FLIP knockdown abolished complex II formation, thus permitting TRAIL induction of OC cell death. The TAK1 inhibitor LLZ1640-2 abrogated the TRAIL-induced c-FLIP upregulation and NF-kB activation, and triggered TRAIL-induced caspase-8 activation and cell death in OCs. Interestingly, the TRAIL-induced caspase-8 activation caused enzymatic degradation of the transcription factor Sp1 to noticeably reduce c-FLIP expression, which further sensitized OCs to TRAIL-induced apoptosis. Furthermore, the TAK1 inhibition induced antiosteoclastogenic activity by TRAIL even in cocultures with MM cells while potentiating TRAIL’s anti-MM effects. These results demonstrated that osteoclastic lineage cells use TRAIL for their differentiation and activation through tilting caspase-8–dependent apoptosis toward NF-kB activation, and that TAK1 inhibition subverts TRAIL-mediated NF-kB activation to resume TRAIL-induced apoptosis in OCs while further enhancing MM cell death in combination with TRAIL

Effective impairment of myeloma cells and their progenitors by hyperthermia

Multiple myeloma (MM) remains incurable, and MM-initiating cells or MM progenitors are considered to contribute to disease relapse through their drug-resistant nature. In order to improve the therapeutic efficacy for MM, we recently developed novel superparamagnetic nanoparticles which selectively accumulate in MM tumors and extirpate them by heat generated with magnetic resonance. We here aimed to clarify the therapeutic effects on MM cells and their progenitors by hyperthermia. Heat treatment at 43°C time-dependently induced MM cell death. The treatment upregulated endoplasmic reticulum (ER) stress mediators, ATF4 and CHOP, while reducing the protein levels of Pim-2, IRF4, c-Myc and Mcl-1. Combination with the proteasome inhibitor bortezomib further enhanced ER stress to potentiate MM cell death. The Pim inhibitor SMI-16a also enhanced the reduction of the Pim-2-driven survival factors, IRF4 and c-Myc, in combination with the heat treatment. The heat treatment almost completely eradicated “side population” fractions in RPMI8226 and KMS-11 cells and suppressed their clonogenic capacity as determined by in vitro colony formation and tumorigenic capacity in SCID mice. These results collectively demonstrated that hyperthermia is able to impair clonogenic drug-resistant fractions of MM cells and enhance their susceptibility to chemotherapeutic drugs

Progressing Suburbanization and the Controversial Land Use Management in a Japanese Local City - A Case Study of Miyakonojo City, Japan-

Today Japanese cities are suffering numerous development problems, including deteriorated city centers and expanding suburban areas. Further, Japan today faces a shrinking and aging population. Thus these cities should seek better balance between proper land use and economic vitalization. This paper examines the long-term development trend for 1985-2011 in Miyakonojo City and evaluates that city\u27s latest land use guidelines to offer the following conclusions: 1) During 1995-2011, the number of building applications transitioned between 600 and 800. Half were in the un-zoned area where suburbanization is being caused mainly by housing; 2) The collective housing is increasing in these un-zoned area as well as in the zoned areas; 3) Concentrations of development are emerging in the un-zoned areas. 4) The Land Use Control Guideline shows the direction of future land use management. Although the guideline will manage suburbanization, housing development remains stake

道路交通における車両・人間系を対象とする人の工学的特性に関する研究

第1章 序論 第2章 発進する自動車のマン･マシン･システム･モデル 第3章 追従行動におけるマン･マシン･システム･モデル 第4章 大型車のマン･マシン･システム･モデル 第5章 騒音･排気ガスヘの適用 第6章 人体の動力学特性 第7章 総括Made available in DSpace on 2012-09-05T04:33:12Z (GMT). No. of bitstreams: 3 teramachi1.pdf: 13837391 bytes, checksum: 6674d586962a086da4db2f9a79be4a7f (MD5) teramachi2.pdf: 7315713 bytes, checksum: 88bcf42f73a66fa95ec2234634c54da2 (MD5) teramachi3.pdf: 13453779 bytes, checksum: ed10961ec75625d7668f95ee24b4571c (MD5) Previous issue date: 1999-10-25主1-参1工学_建設デザイ

道路交通における車両・人間系を対象とする人の工学的特性に関する研究

第1章 序論 第2章 発進する自動車のマン･マシン･システム･モデル 第3章 追従行動におけるマン･マシン･システム･モデル 第4章 大型車のマン･マシン･システム･モデル 第5章 騒音･排気ガスヘの適用 第6章 人体の動力学特性 第7章 総括主1-参1工学_建設デザイ

Study on the Incidence of Opportunity Crime on Residential Streets Considering Traffic Volume and Visible Range

As a basic step, in this study we propose a model to describe the snatch incident on residential streets. This model is based on one of the methodologies of social science and the Crime Prevention Through Environmental Design’s concept. The objective variable is the feasibility of snatch and explanatory variables are physical factors concerning road network design and traffic regulation, like traffic volume and visible range on streets. As the result of the application to actual situations, the model provided reasonable predictions for distribution of point of incidence in a street section. It is possible to examine the influence that road network design and traffic regulation have on snatch by extending this model to road network.Crime Prevention Through Environmental Design (CPTED), Street network design, Opportunity crime, Traffic volume, Visible range

サイン曲線弓形と台形という形状の違いがハンプ上を通過する小型貨物車から発生する衝撃音へ与える影響

歩車分離されていない地区内道路では、歩行者の安全を保つために車の速度を抑制するハンプの設置が検討されるが、その時、騒音が問題になることが少なくない。既に著者らはサイン曲線弓形ハンプを使用した敷地内実験(走行速度約20-40km/h)で、1)乗用車がハンプ上を通過しても衝撃音は生じない、2)一方、小型貨物車(空載)はハンプで跳躍し、大きな衝撃音を発生させる速度領域が存在するので、その対策が必要であることを報告した1)｡そこで本研究では、1)サイン曲線弓形と台形というハンプ形状の違い、2)更に、台形ハンプで小型貨物車(空載)からの衝撃音の発生が抑制される場合には、車に荷を積むことが、小型貨物車から発生する衝撃音にいかなる影響を与えるかについて敷地内実験で調査した｡When a hump is founded in a road to keep traffic safety in a district, noise problem occurs because of impact noise generation, etc. Authors have already confirmed the following fact by experiments in a site: 1)The impact noise is not generated, even if passenger car passes a sine curve segmental hump, 2)but,if a light truck(empty) jumps in a hump at a speed over 20km/h, large impact noise is generated. Furthermore, the following matters were investigated in this study: 1)Influence to impact noise by shape difference between sine curve segmental hump and trapezoidal one, 2)and, increase of impact noise level when a light truck(load) passes a trapezoidal curve hump