β\beta-decay half-lives as an indicator of shape-phase transition in neutron-rich Zr isotopes with particle-vibration coupling effect

[Background] $\beta$-decay half-life is sensitive to the shell structure near the Fermi levels. Nuclear deformation thus impacts the $\beta$-decay properties. [Purpose] A first-order shape-phase transition in neutron-rich Zr isotopes is predicted by some models. We investigate the $\beta$-decay half-lives of neutron-rich nuclei around $^{110}$Zr, where the shape-phase transition is predicted to occur, to see if the $\beta$-decay half-life can be an indicator of the shape changes. [Method] The proton-neutron quasiparticle random-phase approximation (RPA) is adopted to calculate the Gamow-Teller transitions. In addition, we apply the quasiparticle phonon-vibrational coupling (PVC) to consider the phonon couplings. [Results] The spherical and oblate configurations give similar half-lives but shorter ones than the prolate configuration at the RPA level. The PVC effect further reduces the half-lives in general, but the effect is smaller for the deformed configuration than that for the spherical one. As a result, it makes the shape change from the oblate configuration to the spherical configuration visible. Therefore, a sudden shortening of $\beta$-decay half-lives is always found at the nuclear shape changes. [Conclusions] $\beta$-decay half-life is an indicator of the shape-phase transition. The shape mixing and the roles of the triaxial deformation are subject to study in the future.Comment: 7 pages, 4 figure

Role of CD59 in experimental glomerulonephritis in rats

Role of CD59 in experimental glomerulonephritis in rats. CD59 is a molecule which is present on the host cell membranes and inhibits formation of membrane attack complex. A monoclonal antibody, 6D1, recognizes a rat analogue of human CD59. 6D1 inhibits function of rat CD59 and can enhance complement-mediated hemolysis in vitro. To assess the role of CD59 in complement-mediated glomerular injury, 6D1 was tested in a model of experimental glomerulonephritis induced by a lectin and its antibodies. The left kidney of a rat was perfused either with 200 µg of Lens culinaris hemoagglutinin (LCH) plus 1mg of 6D1 (IgGl fraction) (Group I and III) or with LCH only (Group II) through a cannula placed in the left renal artery. All the perfusate was discarded from a cannula in the renal vein. The holes in the artery and vein were repaired by microsurgery and the blood circulation was re-established. Rats were injected either with 0.125ml of rabbit anti-LCH serum (Group I and II), or with normal rabbit serum (Group III) via tail vein one minute after the recirculation. Fifteen minutes after injection, significant C9 deposition in the glomeruli was observed only in Group I, whereas C3 deposition in Group I and II were comparable. At Day 4, total glomerular cells, proliferating cells, glomerular expression of intercellular adhesion molecule-1 and fibrin deposition in Group I were all significantly increased when compared with Group II. At Day 7, number of total glomerular cells and leukocytes in the glomeruli of Group I were significantly higher than in Group II. The glomeruli in Group III appeared normal throughout experiments. These data indicate that the functional inhibition of a rat analogue of human CD59 worsens complement-mediated glomerular injury in vivo

Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas

骨・軟部肉腫は, 一部に治療抵抗性で予後の悪い症例が存在するため, 新たな治療法の確立が重要な課題である.　我々は, 5型アデノウイルスを基本骨格として, テロメラーゼ活性に依存して増殖する腫瘍融解ウイルス（OBP-301）や, coxsackie and adenovirus receptor（CAR）陰性の腫瘍細胞に感染するファイバー改変型ウイルス（OBP-405）を用い, 骨・軟部肉腫細胞に対する抗腫瘍効果を検討した.　 　14種類の骨・軟部肉腫細胞株に対してOBP-301の細胞障害活性を検討し, 12種類の細胞株でOBP-301に感受性を認めた.　また, OBP-301の細胞障害活性はCARの発現と相関していた.　さらに, テロメラーゼ活性の低い細胞に対しても, 5型アデノウイルスの複製に必須のE1Aによりテロメラーゼ活性の増強効果がおこり, 強い抗腫瘍活性を示すことを明らかにした.　次に, 骨肉腫脛骨同所性移植動物モデルを作成しOBP-301を投与したところ, OBP-301投与群では対象群と比べて有意に腫瘍増殖を抑制した.　最後に, OBP-301に感受性を認めなかったCAR陰性細胞株に対してOBP-405を用いて検討し, OBP-405が有効に作用することを確認した.　 　OBP-301やOBP-405を用いたウイルス療法は, 骨・軟部肉腫に対する新たな治療法となる可能性がある.

Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells

Tumor suppressor p53 is a multifunctional transcription factor that regulates diverse cell fates, including apoptosis and autophagy in tumor biology. p53 overexpression enhances the antitumor activity of oncolytic adenoviruses; however, the molecular mechanism of this occurrence remains unclear. We previously developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301, that kills human osteosarcoma cells, but some human osteosarcoma cells were OBP-301-resistant. In this study, we investigated the antitumor activity of a p53-expressing oncolytic adenovirus, OBP-702, and the molecular mechanism of the p53-mediated cell death pathway in OBP-301-resistant human osteosarcoma cells. The cytopathic activity of OBP-702 was examined in OBP-301-sensitive (U2OS and HOS) and OBP-301-resistant (SaOS-2 and MNNG/HOS) human osteosarcoma cells. The molecular mechanism in the OBP-702-mediated induction of two cell death pathways, apoptosis and autophagy, was investigated in OBP-301-resistant osteosarcoma cells. The antitumor effect of OBP-702 was further assessed using an orthotopic OBP-301-resistant MNNG/HOS osteosarcoma xenograft tumor model. OBP-702 suppressed the viability of OBP-301-sensitive and -resistant osteosarcoma cells more efficiently than OBP-301 or a replication-deficient p53-expressing adenovirus (Ad-p53). OBP-702 induced more profound apoptosis and autophagy when compared with OBP-301 or Ad-p53. E1A-mediated miR-93/106b upregulation induced p21 suppression, leading to p53-mediated apoptosis and autophagy in OBP-702-infected cells. p53 overexpression enhanced adenovirus-mediated autophagy through activation of damage-regulated autophagy modulator (DRAM). Moreover, OBP-702 suppressed tumor growth in an orthotopic OBP-301-resistant MNNG/HOS xenograft tumor model. These results suggest that OBP-702-mediated p53 transactivation is a promising antitumor strategy to induce dual apoptotic and autophagic cell death pathways via regulation of miRNA and DRAM in human osteosarcoma cells. Mol Cancer Ther; 12(3); 314-25

Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells

Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive breast and gastric cancers; however, acquired resistance presents a formidable obstacle to long-term tumor responses in the majority of patients. Here, we show the mechanism of resistance to trastuzumab in HER2-positive human cancer cells and explore the molecular sensitization by exogenous expression of HER2-extracellular domain (ECD) in HER2-negative or trastuzumab-resistant human cancer cells. We found that long-term exposure to trastuzumab induced resistance in HER2-positive cancer cells; HER2 expression was downregulated, and antibody-dependent cellular cytotoxicity (ADCC) activity was impaired. We next examined the hypothesis that trastuzumab-resistant cells could be re-sensitized by the transfer of non-functional HER2-ECD. Exogenous HER2-ECD expression induced by the stable transfection of a plasmid vector or infection with a replication-deficient adenovirus vector had no apparent effect on the signaling pathway, but strongly enhanced ADCC activity in low HER2-expressing or trastuzumab-resistant human cancer cells. Our data indicate that restoration of HER2-ECD expression sensitizes HER2-negative or HER2-downregulated human cancer cells to trastuzumab-mediated ADCC, an outcome that has important implications for the treatment of human cancers

Individual growing conditions that affect diameter increment of tree saplings after selection harvesting in a mixed forest in northern Japan

We analyzed temporal patterns in diameter growth of saplings following selection harvesting in an uneven-aged mixed stand dominated by Abies sachalinensis, Acer mono, Quercus crispula, and Betula ermanii in Hokkaido, northern Japan. We examined interspecific differences in growth responses to local growing conditions including harvesting intensity, crowding, stem size, and past duration of the small growth period. Consistent with expectations based on shade tolerance of the species, the age at which the individual reached a diameter at breast height of 12.5 cm was highest for A. sachalinensis and lowest for B. ermanii. The interspecific growth differences between saplings that had or had not experienced local harvesting increased gradually for A. sachalinensis and B. ermanii, but peaked at around 4-6 years after harvesting for Q. crispula. Generalized linear mixed model analysis clearly suggested that individual growth conditions required to enhance diameter growth of saplings differed considerably among species. For Q. crispula and B. ermanii, local harvesting intensity was most strongly and positively associated with diameter growth rate, whereas for A. sachalinensis and A. mono, stem size had the strongest negative effect. Abies sachalinensis saplings responded more to surrounding harvesting when they were relatively small, whereas A. mono showed a weak opposite response. The duration of the small growth period before harvesting had negative effect for A. sachalinensis, but not for the other species. Our study indicated that the influence of selection harvesting on growth of shade-tolerant species depends upon pre- and post-harvest growing conditions