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To clarify the influence of tumor necrosis factor (TNF)-α on fibrotic phenotypes induced by transforming growth factor (TGF)-β in retinal pigment epithelial cells (RPECs) by epigenetic regulation. Human primary retinal pigment epithelial cells (RPECs including ARPE19) were used in cultures in the presence or absence of TNF-α and/or TGF-β2. RT2 Profiler™ (Qiagen) was used for PCR Array for fibrosis and epithelial mesenchymal transition (EMT). Microarray analysis by 3D gene DNA chip was outsourced to Toray Industries Inc. Quantification of histone acetyl transferase (HAT)-related and histone deacetylase (HDAC) related gene expression were also analyzed. HDAC and HAT activity was measured using an EpiQuik HDAC and HAT Activity/Inhibition Assay Kit (Epigentek). CD44, MMP-9, HAT, and HDAC in RPECs were analyzed by western blotting. Analysis of expression of the EMT/fibrosis related CD44 and MMP-9 phenotypes induced by TNF-α+TGF-β2 revealed four alterations in RPECs: 1) abolition of TGF-β2-induced α-SMA by TNF-α; 2) synergy between TNF-α+TGF-β2 for induction of CD44 and MMP-9 phenotypes 3) no inhibition of HDAC activity by either TNF-α or TGF-β2; and 4) significant inhibition of HAT activity by either TNF-α or TGF-β2, but no synergy. The HDAC activation through HAT inhibition by TNF-α+TGF-β was counteracted by HDAC inhibitors, leading to the inhibition of EMT/fibrosis. EMT/fibrotic CD44 and MMP-9 phenotypes were epigenetically upregulated by concerted action of TNF-α and TGF-β in RPECs. The intervention in epigenetic regulation may hold potential in preventing intraocular proliferative diseases.

To reveal the mechanism triggering the functional disparity between degenerated and non-degenerated corneal endothelium cells in the water efflux from corneal stroma to the anterior chamber.The varied levels of the microRNA (miR)-34, miR-378, and miR-146 family in human corneal endothelium and cultured cells thereof were investigated using 3D-Gene Human miRNA Oligo Chips. Concomitantly, CD44, p53, c-Myc, matrix metalloprotease (MMP)-2 expression, and Ras homolog gene family member A (Rho A) activity was correlated to the expression intensities of these microRNAs, partly complemented with their altered expression levels with the transfection of the corresponding mimics and inhibitors. The levels of miRs were further associated with intracellular pH (pHi) and mitochondrial energy homeostasis.P53-inducible miR-34a/b repressed CD44 expression, and CD44 was repressed with the elevated c-Myc. The repressed miR-34a activated the CD44 downstream factors Rho A and MMP-2. MiR-34a mimics downregulated pHi, inducing the skewing of mitochondrial respiration to oxidative phosphorylation. The oxidative stress (H2O2) induced on human corneal endothelial cells, which repressed miR-34a/b expression, may account for the impaired signaling cascade to mitochondrial metabolic homeostasis necessary for an efficient water efflux from the corneal stroma.The upregulated expression of CD44, through repressed miR-34a/b by reactive oxygen species and elevated c-Myc by oxidative stress, may impair mitochondrial metabolic homeostasis, leading to human corneal endothelial failure.

To investigate the localized expression of C1q/tumor necrosis factor related protein (CTRP) 6 in human age-related macular degeneration (AMD) retinal tissues.4 AMD and 3 non-AMD whole eyes of Caucasian donors were used. Eyecups were excised at Eye Bank CorneaGen, Inc.To elucidate the effects of CTRP6, C3b was measured by an enzyme-linked immunosorbent-like assay. CFB versus CTRP6 competitive binding assay was applied to clarify the inhibition by CTRP6 of C3bBb complex formation. The cornea, iris, lens, and vitreous were removed and the eyes were cut into a posterior eye-cup including the retina, choroid, and sclera. Six-µm-thick serial sections of frozen samples underwent hematoxylin-eosin (HE) staining and indirect immunohistochemical staining using primary antibodies, anti-CTRP6, -CTRP5, -CTRP10, -Complement factor H (CFH) and -Clusterin (CLU). Results The two in vitro studies confirmed that CTRP6 has an inhibitory effect on alternative pathways of complement (APC) function and that the molecular target of CTRP6 is the inhibition of the formation of C3bBb. Localized expression for CTRP6 and CFH was found in the drusen of the AMD eyes, both associated with APC inhibition, CLU associated with membrane-attack complex (MAC) inhibition, and CTRP5 associated with retinal degeneration.The localized expression of CTRP6 in the drusen of AMD eyes may open a new insight into the possible involvement of APC regulatory factors in the pathogenesis of AMD, together with the known CFH so far analyzed solely as an APC inhibitor.

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No. of bitstreams: 1 VIVIANE EIKO ITO YAMASAKI.pdf: 1690683 bytes, checksum: 2d2a72fd99a23973fb737a5b04588648 (MD5) Previous issue date: 2021-06-30 International joint ventures (IJVs) have been one of the most used entry mode strategies by multinational companies (MNCs) to internationalize and access different foreign markets. However, the decision to establish an IJV involves strategic decisions that can be impacted by internal and external aspects. This thesis aims to investigate the influence of institutional environments and management on the formation and control of IJVs. Three articles were developed in the thesis to achieve this goal, one being a literature review and two empirical studies. The first article investigates the influence of culture on IJVs, seeking to understand how literature has developed over time and to propose a future agenda for current research. From this first article, two quantitative studies were developed based on institutional theory and the perspective of human capital, using a sample of 4,826 IJVs located in Europe and Latin America. Thus, the second article analyzes the formation of the IJVs from the partners’ nationality and quantity, which are relevant aspects of this strategy for establishing the IJVs, but not so much explored in the literature. The third article analyzes the external and internal factors that interfere with the IJVs' shareholding control. In these last two empirical articles, the indirect effects of moderating institutional environments with the management, location, and size of the IJV were investigated, using the analysis of marginal effects, which brought essential findings to the literature. The thesis contributes to the literature, showing the relevance of using the institutional theoretical basis and the human capital perspective for studies on the establishment of IJVs. Additionally, the importance of considering aspects related to the formation of IJVs from the perspective of nationality and the number of partners. Finally, it highlights the need to analyze the moderation of institutional environments related to the formation and property control strategy of IJVs, indicating that they cannot only be analyzed via a direct relationship. As joint ventures internacionais (IJVs) têm sido uma das formas mais utilizadas pelas empresas multinacionais (EMNs) se internacionalizarem e acessarem os diferentes mercados estrangeiros. Entretanto, a decisão de estabelecer uma IJV envolve decisões estratégicas e que podem ser impactadas por aspectos internos e externos. A presente tese tem como objetivo investigar a influência dos ambientes institucionais e da gestão na formação e no controle das IJVs. Para atingir tal objetivo, foram desenvolvidos três artigos na tese, sendo uma revisão de literatura e dois estudos empíricos. O primeiro artigo investiga a influência da cultura nas IJV, buscando entender como a literatura se desenvolveu ao longo do tempo e propor uma agenda futura de pesquisas atuais. A partir deste primeiro artigo, foram desenvolvidos dois estudos quantitativos com base na teoria institucional e na perspectiva de capital humano, utilizando uma amostra de 4.826 IJVs localizadas na Europa e América Latina. Assim, o segundo artigo analisa a formação das IJVs sob a ótica da nacionalidade dos parceiros e do número de parceiros, que constituem perspectivas relevantes nesta estratégia de estabelecimento das IJVs, mas pouco explorada na literatura. O terceiro artigo analisa os fatores externos e internos que interferem no controle acionário das IJVs. Nestes dois últimos artigos empíricos, foram investigados os efeitos indiretos da moderação dos ambientes institucionais com a gestão, a localização e o tamanho da IJV, utilizando a análise de efeitos marginais, o que trouxe achados importantes para a literatura. A tese contribui para a literatura, mostrando a relevância da utilização da base teórica institucional e a perspectiva de capital humano para os estudos de estabelecimento das IJVs. Adicionalmente, a importância de considerar aspectos relacionados à formação das IJVs sob a ótica de nacionalidade e quantidade de parceiros. Por fim, evidencia a necessidade de analisar a moderação dos ambientes institucionais relacionadas à estratégia de formação e controle de propriedade das IJVs, indicando que não podem ser apenas analisadas via uma relação direta.

To explore new molecular targets for therapy in human model systems by discerning the role of extracellular vesicle (EV) microRNAs (miRs) secreted by human retinal pigment epithelium (hRPE) cells and their cellular interplay with macrophages (Mps). Human Mps differentiated from THP-1 cells stimulated by phorbol myristate acetate were co-cultured with induced pluripotent stem cell-derived differentiated hRPE (iPS-hRPE) cells in Transwell® system separated by 0.40 μm or 0.03 μm filters. EV-associated CD63+ proteins (CD63+ EV) were detected by western blotting, and secreted EVs were analyzed by Nanosight tracking. The miR profiles of the secreted EVs were determined using 3D-gene human microRNA chips (Toray Industries, Inc.). Levels of CD63+ EV were increased in co-cultures concomitantly with the increased production of EV particles (50–150 nm). The increased production of EVs was associated with higher production of MCP-1, IL-6, IL-8 from hRPE cells, and VEGF and repressed production of TNF-α from Mps and pigment epithelium-derived factor (PEDF) from RPE cells. Ultracentrifugation of semi-purified EVs increased the secretion of these pro-inflammatory cytokines and EV particles from hRPE cells, but this effect was eliminated in transwells equipped with 0.03 μm filters, whereas no repression of PEDF and TNF-α secretion occurred. 3D-gene miR analysis revealed a selective increase in secretion of miR494-3p in EVs from iPS-hRPE cells during the interplay with Mps. The miRs in EVs secreted by hRPE cells may have a critical role in the vicious inflammatory cycle, whereas repression of TNF-α and PEDF require cell-to-cell contact that is independent of EVs or exosomes. MiR494-3p may be a candidate molecular target of diagnosis and therapy for age-related macular degeneration.

The aim of the study is to clarify the participation of extracellular vesicles (EV) secreted by murine primary retinal pigment epithelial (mpRPE) cells in the cell to cell communication with macrophages (Mps), firstly described by the authors in 2016. In ocular inflammation, Mps act as sources of tumor necrosis factor-α (TNF-α), an activator of RPE cells. TNF-α stimulates the production of monocyte chemotactic protein (MCP-1) by RPE cells, thereby causing greater recruitment of Mps to the sub-RPE space. Murine RAW 264.7 Mps cells were co-cultured with C57BL/6 mouse mpRPE cells, either together or separated in transwells, vertically or horizontally connectable, with 0.40 or 0.03 μm membrane filters. The association of EV with mpRPE or RAW 264.7 was quantified by fluorescence cell sorting (FACS) using Qdot655 streptavidin-conjugated biotinylated EV. Increased levels of CD63

Purpose The aim of this analysis was to compare acute and late toxicities between low-dose-rate brachytherapy (LDR-BT) (110 Gy) in combination with 45 Gy in 25 fractions external beam radiation therapy (EBRT) and LDR-BT (160 Gy) alone for localized prostate cancer. Material and methods One hundred five consecutive patients with localized prostate cancer treated from May 2014 to May 2017 were included in this retrospective analysis. Sixty patients received combination therapy and 45 patients received BT monotherapy. The LDR-BT procedure was performed using 125I seeds. Results The median follow-up time was 28 months in both groups. Three-year effect rates were overall survival: 100% in both groups. The biochemical failure rate was 2.3% in the combination group and 0% in the monotherapy group (p = 0.373). No patients died during the study period. In both groups, almost all the patients experienced acute urethritis. There was a significant difference between the combination therapy group (8.3%) and BT monotherapy group (11.1%) in late genitourinary (GU) toxicities ≥ grade 2 (p = 0.035). Only 2 patients (3.3%) in the combination therapy group developed late ≥ grade 2 rectal hemorrhage. There were no significant differences between two groups in hematuria ≥ grade 2 (p = 0.068) or rectal hemorrhage ≥ grade 2 (p = 0.206). Conclusions To our knowledge, this is the first report to compare the GU and gastrointestinal toxicities between the combination therapy and BT monotherapy (160 Gy) for localized prostate cancer. Unexpectedly, there were more late GU toxicities (except for hematuria) in the BT monotherapy group.

// Masaharu Hata 1, 2 , Izumi Koike 2 , Etsuko Miyagi 3, 4 , Reiko Numazaki 4, 5 , Mikiko Asai-Sato 4 , Hisashi Kaizu 2 , Yuki Mukai 2 , Shoko Takano 2 , Eiko Ito 2 , Madoka Sugiura 2 and Tomio Inoue 2 1 Division of Radiation Oncology, Department of Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan 2 Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan 3 Division of Gynecologic Oncology, Department of Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan 4 Department of Obstetrics and Gynecology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan 5 Department of Obstetrics and Gynecology, Yokohama Minami Kyousai Hospital, Yokohama, Kanagawa, Japan Correspondence to: Masaharu Hata, email: mhata@syd.odn.ne.jp Keywords: cervical cancer; radiation therapy; stage IVA; uterine cervix; vesicovaginal fistula Abbreviations: Biological effective dose, BED; high-dose-rate, HDR; computed tomography, CT; Radiation Therapy Oncology Group, RTOG Received: September 11, 2017 Accepted: October 27, 2017 Published: December 01, 2017 ABSTRACT Purpose: To evaluate the safety and efficacy of radiation therapy for stage IVA uterine cervical cancer and to identify an optimal radiation regimen. Results: Seventeen of the 28 patients developed recurrence after radiation therapy (local recurrence in 10 and distant metastasis in 12). The local control and distant metastasis-free rates at 3 years in all patients were 61% and 49%, respectively. Fourteen patients died after radiation therapy, and all but 2 died of tumor progression. The disease-free, cause-specific, and overall survival rates at 3 years in all patients were 32%, 49%, and 45%, respectively, and the estimated median survival time was 32 months. Tumor size ( P = 0.007) and involvement in the lower third of vagina ( P = 0.006) were significant prognostic factors for local control. Older age ( P = 0.018) and performance status ( P = 0.020) were significant prognostic factors for distant metastasis. The presence of hydronephrosis was the sole significant prognostic factor for survival ( P = 0.026). Only 2 patients developed grade 3 late toxicities (vesicovaginal fistula and radiation proctitis, respectively). Materials and Methods: Twenty-eight patients with stage IVA uterine cervical cancer received radiation therapy. All patients initially received external pelvic irradiation at a median dose of 50.4 Gy in 28 fractions. Twenty patients also received high-dose-rate intracavitary brachytherapy at a median dose of 22 Gy in 4 fractions. These fraction sizes were lower than conventional sizes. The total median dose for all 28 patients was 68.7 Gy. Conclusions: Radiation therapy is safe and effective for treatment of stage IVA uterine cervical cancer. The reduced radiation dose per fraction may contribute to the prevention of vesicovaginal fistula formation.

Introduction/Background Patients with bone metastasis from uterine cervical cancer usually have a poor prognosis and are candidates for palliative care. We therefore carried out a review to determine the role of radiation therapy for patients with bone metastasis from uterine cervical cancer and to identify the optimal radiation regimen. Methodology A total of 21 patients with bone metastasis from uterine cervical cancer received radiation therapy to the pelvis. All patients received external irradiation and 13 patients also received high-dose-rate intracavitary brachytherapy. The median total dose of 60.4 Gy (range, 32.4-76.2 Gy) was delivered to cervical tumors of all patients and corresponded to 62.1 Gy (range, 31.9-83.3 Gy) in the 2 Gy per fraction-equivalent dose (EQD2). Thirteen patients underwent chemotherapy during and/or following radiation therapy. Results In 19 of 21 patients, the primary tumors disappeared or were markedly reduced after radiation therapy. In all but one of 18 patients with pelvic pain and bleeding, these symptoms disappeared or were remarkably relieved. However, three patients had primary tumor progression at 7, 9, and 15 months after irradiation with total doses of 56.8, 58.4, and 68.3 Gy in EQD2, respectively. Two of these patients had relapses of bleeding and pain. The primary progression-free rates in all patients were 73% at 1 year, and 37% at 2 years. The overall survival rates were 38% at 1 year, and 9% at 2 years, with an estimated median survival time of 7 months. The number of metastatic bone sites (p=0.016) and administration of chemotherapy (p Conclusion Radiation therapy is very effective for relief of pelvic symptoms in patients with bone metastasis from uterine cervical cancer. For patients who are expected to survive for more than 1 year, almost curative-dose irradiation to primary tumors is recommended. Disclosure Nothing to disclose.

Background/Aim: The aim of this study was to define the outcome of radiation therapy for vulvar carcinoma, and to investigate the effectiveness of therapeutic and prophylactic inguinal lymph node (ILN) irradiation. Because reports about the treatment of ILN were limited. Patients and Methods: Thirty consecutive vulvar carcinoma patients were treated using external beam radiation therapy (EBRT) for definitive disease (n=25) or postoperatively (n=5). Twenty-four (80%) had squamous cell carcinoma (SCC). Tumor stages (2002 UICC) ranged from 0 to IVB, with no distant metastases. Results: The median total prescribed dose for primary tumor was 64.8 Gy. The 2-year overall survival rate was 25.3%. The outcome was significantly better in patients with ILNs60 Gy (p=0.002). Conclusions: ILN diameters ≤30 mm and prescribed doses over 60 Gy were associated with ILN control in patients with vulvar carcinoma.

Background Overall survival (OS) of patients with diffuse intrinsic pontine glioma (DIPG) is poor, with radiation therapy (RT) the only intervention that transiently delays tumor progression. Hypofractionated RT and re‐irradiation at first progression have gained popularity in improving the quality of life of such patients. Methods We performed a retrospective review of children with DIPG treated at Kanagawa Children's Medical Center from 2000 to 2018. Results A total of 24 cases were reviewed. Median age at diagnosis was 6.3 years (1.6–14.0). Twenty patients received RT only once. Thirteen patients received conventionally fractionated RT, and seven patients received hypofractionated RT as up‐front RT. Severe toxicities were not observed in patients who received hypofractionated RT. Median OS and time to progression were similar between conventionally fractionated and hypofractionated RT groups.(9.7 [95% confidence interval(CI): 7.1‐11.2] versus 11.0[95% CI: 5.2‐13.6] months, P = 0.60; 4.2[95% CI: 1.8‐8.3] versus 7.1 [95% CI:4.5‐8.7] months, P = 0.38). Four patients received re‐irradiation at first progression and all patients showed transient neurological improvement and survival more than a year after diagnosis. A 4‐year‐old boy was re‐irradiated 5‐and‐a‐half months after the first re‐irradiation; following transient neurological improvement. He survived a further 5 months. Conclusion Hypofractionated RT for children with newly diagnosed DIPG is well tolerated and feasible from the viewpoint of reducing a patient's burden of treatment. Re‐irradiation at first progression is suggested to be beneficial.

The aim of the study is to clarify the participation of extracellular vesicles (EV) secreted by murine primary retinal pigment epithelial (mpRPE) cells in the cell to cell communication with macrophages (Mps), firstly described by the authors in 2016. In ocular inflammation, Mps act as sources of tumor necrosis factor-α (TNF-α), an activator of RPE cells. TNF-α stimulates the production of monocyte chemotactic protein (MCP-1) by RPE cells, thereby causing greater recruitment of Mps to the sub-RPE space. Murine RAW 264.7 Mps cells were co-cultured with C57BL/6 mouse mpRPE cells, either together or separated in transwells, vertically or horizontally connectable, with 0.40 or 0.03 μm membrane filters. The association of EV with mpRPE or RAW 264.7 was quantified by fluorescence cell sorting (FACS) using Qdot655 streptavidin-conjugated biotinylated EV. Increased levels of CD63+ EV were detected in co-cultures by western blotting or FACS analysis, in accordance with the increased production of nanoparticles (50–150 nm) detected by Nanosight tracking analysis. The gene expressions of cytokines, MCP-1, IL-6, IL-8, and VEGF in mpRPE cells and the corresponding proteins were increased in co-cultures even in transwells, vertically connected with 0.40 μm membrane filters, while the repressed TNF-α protein production was not affected. Most of the CD63+ EVs produced by mpRPE cells in co-cultures were associated with Raw264.7, but not with mpRPE cells. Semi-purified CD63+ EV secreted from mpRPE cells, increased the secretion of MCP-1, IL-6, and VEGF in co-cultures with RAW 264.7. Culture chamber separation horizontally connected with 0.03 μm membrane filters reduced this increased secretion. Collectively, mpRPE derived CD63+ EV partly participate in the sub-retinal innate inflammation. To evaluate the functional damage of RPE cells upon chronic exposure to here defined EVs will be the critical issue to uncover their roles in chronic retinal degenerative diseases.

To compare the outcomes of radical prostatectomy (RP), intensity-modulated radiation therapy (IMRT), and low-dose-rate brachytherapy (BT) using propensity score matching analysis in patients with clinically localized prostate cancer. A group of 2273 patients with clinically localized prostate cancer between January 2004 and December 2015 at the Yokohama City University hospital were identified. The records of 1817 of these patients, who were followed up for a minimum of 2 years, were reviewed; 462 were treated with RP, 319 with IMRT, and 1036 with BT. The patients were categorized according to the National Comprehensive Cancer Network risk classification criteria, and biochemical outcomes and overall survival rates were examined. Biochemical failure for RP was defined as prostate-specific antigen (PSA) levels > 0.2 ng/ml, and for IMRT and BT as nadir PSA level + 2 ng/ml. Propensity scores were calculated using multivariable logistic regression based on covariates, including the patient's age, preoperative PSA, Gleason score, number of positive cores, and clinical T stage. Median follow-up was 77 months for the RP, 54 months for IMRT, and 66 months for BT patients. After the propensity scores were adjusted, a total of 372 (186 each) and 598 (299 each) patients were categorized into RP vs IMRT and RP vs BT groups, respectively. Kaplan–Meier analysis did not show any statistically significant differences in terms of overall survival rate between these groups (RP vs IMRT: p = 0.220; RP vs BT: p = 0.429). IMRT was associated with improved biochemical failure-free survival compared to RP in all risk groups (high-risk: p

AIM To determine the role of radiation therapy for patients with bone metastasis from uterine cervical cancer and identify an optimal radiation regimen. PATIENTS AND METHODS A total of 20 patients with bone metastases from uterine cervical cancer received radiation therapy to the pelvis. The median total dose of 60.2 Gy in the 2 Gy per fraction-equivalent dose (EQD2) was delivered to cervical tumors of all patients. Thirteen patients underwent chemotherapy during and/or following radiation therapy. RESULTS In 18 of 20 patients, the primary tumors disappeared or were markedly reduced after radiation therapy. In all but one of 17 patients with pelvic pain and bleeding, these symptoms disappeared or were remarkably relieved. However, three patients had primary tumor progression at 7, 9, and 15 months after irradiation with total doses of 56.8, 58.4, and 68.3 Gy in EQD2, respectively. Two of these patients had relapses of bleeding and pain. The primary progression-free rate considering all patients was 69% at 1 year and 34% at 2 years. The corresponding overall survival rates were 34% at 1 year, and 8% at 2 years, with an estimated median survival time of 7 months. The number of metastatic bone sites (p=0.027) and administration of chemotherapy (p

Supplemental Digital Content is available in the text, The aim of this study was to analyze dose-volume histogram (DVH) of the remnant liver for postoperative cholangiocarcinoma (CCA) patients, to find toxicity rates, and to confirm efficacy of postoperative radiation therapy (RT). Thirty-two postoperative CCA patients received partial liver resection and postoperative RT with curative intent. The “liver reduction rate” was calculated by contouring liver volume at computed tomography (CT) just before the surgery and at CT for planning the RT. To evaluate late toxicity, the radiation-induced hepatic toxicity (RIHT) was determined by the common terminology criteria for adverse events toxicity grade of bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, and albumin, and was defined from 3 months after RT until liver metastasis was revealed. The radiation-induced liver disease (RILD) was also evaluated. Tumor stages were distributed as follows: I: 1, II: 8, IIIA: 1, IIIB: 6, IIIC: 14, IVA: 2. Median prescribed total dose was 50 Gy. Median follow-up time was 27 months. Two-year overall survival (OS): 72.4%, disease-free survival: 47.7%, local control: 65.3%, and the median survival time was 40 months. The median “liver reduction rate” was 21%. The OS had statistically significant difference in nodal status (P = .032) and “liver reduction rate” >30% (P = .016). In the association between the ≥grade 2 RIHT and DVH, there were significantly differences in V30 and V40 (P = .041, P = .034), respectively. The grade ≥2 RIHT rates differ also significantly by sex (P = .008). Two patients (6.2%) were suspected of RILD. We suggest that RT for remnant liver should be considered the liver V30, V40 to prevent radiation-induced liver dysfunction.

Purpose The purpose of this study was to clarify the interactions between macrophages (MPs) and RPE cells in coculture systems to investigate the functional plasticity of RPE cells. Methods Adherent peritoneal cells or murine MP cell line Raw 264.7 was cocultured with primary RPE cells taken from C57BL/6 mice, with or without lipopolysaccharide (LPS) or TNF-α stimulation. The cytokine levels of the culture supernatants (CSs) were then analyzed with the Bio-Plex murine 23-Plex Panel Assay Kit (Bio-Rad Laboratories). Monocyte chemoattractant protein-1 (MCP-1), IL-6, VEGF, and TNF-α in CS were further quantified by ELISA. The expression profiles, in cocultures, of complement-associated genes, TNF-α, and angiogenesis-associated genes were analyzed by quantitative real-time PCR. Results The production of MCP-1, IL-6, and VEGF was synergistically elevated when primary MPs or RAW264.7 cells and RPE cells were cocultured compared with those derived from sole cultures of MPs and RPE cells. The synergistic effect was confirmed without direct cell contact and was more prominent in the presence of LPS or TNF-α. TNF-α production by MPs was suppressed by RPE cells. Coculture of RPE cells with RAW264.7 cells increased the gene expression of C3, CFB, and VEGF genes, whereas it reduced those of complement regulatory factors CFH, CD59, clusterin, and TNF-α and antiangiogenic pigment epithelium-derived factor (PEDF). Conclusions Our findings indicate the presence of ingenious interactions between MPs and RPE cells that forces the inflammation and complement activation in the vicinity of RPE cells under pathologic conditions.

Background: In Japan, oral antihistamines are frequently used as the initial treatment for seasonal allergic rhinitis (SAR), and intranasal steroids are added when nasal symptoms worsen. This study aimed to evaluate whether starting treatment with fluticasone propionate nasal spray (FP) from the beginning of pollinosis symptoms and adding fexofenadine hydrochloride tablet (FEX) when SAR is aggravated could achieve improved amelioration of nasal symptoms throughout the pollen season in comparison with a treatment that involves starting with FEX and later adding FP. Methods: In this pragmatic, randomized, open-label, parallel-group trial, 51 Japanese cedar pollinosis patients (age, 16–85 years) were randomly divided and administered FP 100 mcg twice daily as an initial drug with FEX 60mg twice daily as an additional drug and the same treatment in the reverse order. Nasal symptoms were evaluated in a daily dairy using a 4-point scale. The primary outcome was area under curve of the line representing the daily total nasal symptom score in the pollen season on a graph. Results: Initial treatment with FP was significantly (P=0.0015) more effective than initial treatment with FEX in improving the primary outcome. The average daily total nasal symptom score in the initial treatment with FP group was better than that in the initial treatment with FEX group throughout the pollen season. Conclusions: Initiating treatment with FP and adding FEX might lead to improved outcomes for nasal symptoms in comparison with the same drugs administered in the reverse order.

Using a magnetically formed channel called a magnetic channel, a new flow-type cell is proposed. The magnetic channel consists of magnetic walls that are formed by heterogeneous distributions of magnetic flux density around a ferromagnetic track under a magnetic field. The magnetic wall separates the paramagnetic oxidant solution from the diamagnetic reductant solution at a liquid–liquid interface without any solid membranes. In the magnetic channel formed on the cathode, the oxidant solution flows in a quasi-frictionless mode. The anode is placed in the reductant solution surrounding the magnetic channel. Such a geometrical configuration between the oxidant and reductant solutions is interchangeable depending on the magnetism of the solutions. To examine this concept, a Daniel cell system was adopted, where the copper ion in copper sulfate solution is employed as the oxidant and the zinc atom of zinc electrode as the reductant. The copper ion is paramagnetic, so that 1 mol dm−3 copper sulfate solution is injected into the magnetic channel formed on the copper cathode. Zinc sulfate solution (1 mol dm−3; diamagnetic) together with the zinc anode are placed surrounding the magnetic channel. The performance of this flow-type battery was examined up to a current density of 22 mA cm−2.

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been reported as a strong neurotrophic factor in the various sites of nervous system. The facial nerve injury is one of the common problems in patients at the Otolaryngology since the nerve damage could occur easily due to the anatomical characteristics. Once it happens, the regeneration is little observed and functional recovery is poor. Thus, we investigated that PACAP might have some influence for regeneration after the facial nerve transaction in the guinea pig. PACAP treatment accelerated time for the appearance of compound muscle action potentials (CMAP) after the nerve transaction (first appeared at 1 versus 2 weeks in control) and shortened the latency at 4 weeks. The number of myelinated fibers increased at 4 weeks. Histochemical demonstration of GAP-43, a growth cone protein, was observed at the injury area at 2-4 days. PACAP increased the level of glial cell line-derived neurotrophic factor (GDNF), a neurotrophin, in facial target muscles at 1 day-4 weeks. These data indicated that PACAP promotes the regeneration factors and increases the possibility of functional recovery following the facial nerve injury.

In my undergraduate days I was bored with language descriptions based on the then-popular structuralistprinciples and came to be interested in the field of the history of English. Some of the historical changes inthe English language that appeared to turn in a certain direction although there was apparently no humanplanning really fascinated me. I pursued my interests in earlier forms of English,especially Late Middle English,at the graduate school of the University of Michigan,where I wrote a doctoral dissertation on the syntactic changes from Late Middle to Early Modern English,using the parallel texts of a medieval mystic workThe Cloud of Unknowing.I started to teach at Kobe College in 1972. During my early days here I was engaged in studies of the relationshipbetween form and meaning in Chaucer's writings and also in a project for compiling an Englishetymological dictionary initiated by Professor Yoshio Terasawa,which was finally published in 1997,17years after the first editorial meeting.English has a history of about 1500 years and is still changing. It would be unlikely that English will undergo such extensive grammatical or phonological changes as in the past.However,we can observe somesubtle changes in the use of English in various texts,influenced by various factors such as new modes ofcommunication,changes in reader expectations and sales objectives. I would like to continue to watchchanges in Modern English.

Although the action of cetirizine dihydrochloride (cetirizine), a potent histamine H1 receptor antagonist, has been well known, its effect on the cytokine profiles in the nasal immune inductive site has not been elucidated yet. We studied the effect of cetirizine on the cytokine profiles in the nasal-associated lymphoid tissue (NALT), which is a principal mucosal lymphoid tissue of the respiratory tract in rodents. Two different doses of cetirizine were given intraorally for 5 days before the nasal challenge of ovalbumin in sensitized mice. The sensitized group was given normal saline instead of cetirizine, and the nonsensitized group had no sensitization or medication. The cytokine gene expressions in the NALT taken from the mice were investigated with real-time quantitative reverse-transcription polymerase chain reaction. The effect of cetirizine on the allergic symptom score, histamine threshold, and the eosinophil count in the nasal septal mucosa were examined also. Compared with the normal mice, the sensitized mice showed significantly increased levels of interleukin (IL)-4 and IL-5 gene expression although the increase of interferon (INF)-γ gene expression was not significant. In the cetirizine groups, the levels of expression of IL-4, IL-5, and INF-γ in the NALT were significantly decreased compared with the sensitized group. The cetirizine groups also showed decreased allergic symptom score, histamine threshold, and eosinophil count in the nasal septal mucosa compared with the sensitized group. In conclusion, cetirizine reduced the levels of expression of IL-4, IL-5, and INF-γ in the NALT of ovalbumin-sensitized mice. Cetirizine also reduced the acute allergic symptom, histamine sensitivity, and eosinophil count in the nasal septal mucosa.

This paper analyses the applicability on Brazilian multinational Companies (MNCs) in twotypologies developed to explain the internationalization of emerging market’s enterprises.Using Fundação Dom Cabral 2011 data about companies with the higher transnationalityindex, information was gathered though documental research. This article builds a systematicclassification on Brazilian MNCs upon the springboard perspective and the genericinternationalization strategies. Results show that the “world-stage aspirant” group prevailedon the Springboard typology. Concerning the generic internationalization strategy, the samplewas distributed among all strategies., El objetivo de ese trabajo es discutir la aplicación de las tipologías de internacionalización delas EMNEs (Empresas Multinacionales Emergentes) en el caso brasileño. Por medio deinvestigación documental, informaciones sobre las 20 empresas brasileñas con mayor índicede transnacionalidad fueron recopiladas, de acuerdo con datos de 2011 de la Fundación DonCabral. De esta manera fueron identificadas las características de las multinacionalesbrasileñas, lo que permitió la clasificación integrada entre las tipologías trampolín y lasestrategias genéricas de internacionalización. En la perspectiva trampolín, lainternacionalización califica las EMNEs para adquisición de recursos estratégicos y reducciónde restricciones institucionales y de mercadeo del país de origen. Sobre la aplicabilidad de lastipologías, los resultados demuestran que el grupo aspirante prevalece en la perspectivatrampolín. Con relación acerca de las estrategias genéricas, fue observada la adherencia de laamuestra con diversas tipologías propuestas., O objetivo deste artigo é discutir a aplicação das tipologias de internacionalização das EMNEs(Empresas Multinacionais Emergentes) no caso brasileiro. Por meio de pesquisa documental,foram levantadas informações sobre as 20 empresas brasileiras com maior índice detransnacionalidade, de acordo com dados de 2011 da Fundação Dom Cabral. Assim, foramidentificadas as características das multinacionais brasileiras, permitindo a classificaçãointegrada entre as tipologias trampolim e as estratégias genéricas de internacionalização. Naperspectiva trampolim, a internacionalização qualifica as EMNEs para a aquisição de recursosestratégicos e redução de restrições institucionais e mercadológicas do país de origem. Sobrea aplicabilidade das tipologias, os resultados demostram que o grupo aspirante prevalece naperspectiva trampolim. E com relação às estratégias genéricas verificou-se a aderência daamostra às diversas tipologias propostas.

Background Extramammary Paget's disease (EMPD) is a relatively rare malignancy, and there are few reports related to radiation therapy. In the present study, we investigated the outcome of radiation therapy for EMPD. Patients and methods Forty-one patients with EMPD in the genitalia underwent radiation therapy with curative intent. Fifteen patients had regional lymph node metastases before radiation therapy, but none had distant metastasis. Total doses of 45–80.2 Gy (median, 60 Gy) were delivered to tumor sites in 23–43 fractions (median, 33 fractions). Results At a median follow-up period of 41 months, 16 patients had developed recurrences, including 5 with local progression within the radiation field and 12 with lymph node or/and distant metastases outside the radiation field. The local progression-free and disease-free rates were 88% and 55% at 3 years, and 82% and 46% at 5 years, respectively. Nine patients died at 6–73 months after irradiation; the causes of death were tumor progression in five patients, infectious pneumonia in two, renal failure in one and old age in one. The overall and cause-specific survival rates were 93% and 96% at 3 years, and 68% and 84% at 5 years, respectively. Tumor invasion into the dermis and regional lymph node metastasis were significant prognostic factors for both distant metastasis and survival. No therapy-related toxicities of grade ≥3 were observed. Conclusions Radiation therapy is safe and effective for patients with EMPD. It appeared to contribute to prolonged survival owing to good tumor control, and to be a promising curative treatment option.

Microstructures formed by excimer laser ablation of uniaxially stretched poly(ethylene-2,6-naphthalate) (PEN) films were analyzed as a function of draw ratio, laser fluency, and number of pulses. Before ablation, stretched films with draw ratio higher than 3 exhibit band like structure on the surface running perpendicular to the drawing direction. By TEM observation of the cross section, this structure was found to extend into the bulk region. Upon laser pulse irradiation, microstructures are formed on the surface whose pattern and pitch are similar to those for the original band like structure. With further irradiation of pulses, pleated structures were formed with pitch larger than that for the original band like structure. Spectroscopic analysis of the pleated structure was conducted on the particles scratched off from the ablated surface. It was indicated that the pleated parts were amorphous but partially elongated.

Conformation change occurring during the formation of the liquid crystalline phase was investigated by using the in situ Fourier transform infrared spectroscopy. An isotropic glass of a random liquid crystalline copolyester consisting of 60 mol% p-hydroxybenzoic acid/40 mol% ethylene terephthalate was prepared with the cast from a solution and was heated from the room temperature up to 300°C. The onset of the transformation from the gauche conformers to the trans conformers of the ethylene glycol group was observed at ca. 60°C. The change in packing was indicated by the change in the intensity of the bands assignable to the aromatic rings around 150°C. Liquid crystalline phase formation observed with the optical method started to occur at ca. 200°C in association with the loss of the packing.

高分子液晶60mol%p-hydroxybenzoic acid/40mol% ethylene terephthalateを磁場 (6T) 中で配向させ, 配向フィルムの構造, 物性解析を行った. 磁場配向フィルムは同程度の配向度をもつ機械配向フィルムに匹敵する弾性率を示した. 破断強度は磁場配向フィルムの方が低い値を示したが, これは配向構造の相違に起因するものと考えられる. 熱膨張率の配向度依存性は機械配向させた液晶性高分子あるいは結晶性高分子と同様の傾向を示した. 結晶性高分子poly (ethylene-2, 6-naphthalate) (PEN) およびisotactic polystyreneが磁場 (6T) 中, 融点付近の熱処理により磁場配向することを見いだした. X線解析, 磁気複屈折測定により, 配向は結晶化誘導期に起こることを示した. PENのin situ赤外分光法により, 結晶化誘導期において非晶中にtrans構造が増大することがわかった. これは誘導期における液晶的な配向秩序が磁場配向に寄与していることを示唆する.

Magnetic orientation of poly(ethylene-2,6-naphthalate) [PEN], reported in the previous paper, was studied in detail. Birefringence, X-ray and infrared analyses were carried out on the samples quenched at different periods of the crystallization time during the crystallization at 255°C in the magnet (6T). These analyses showed that the orientation observed in the birefringence measurements starts during the induction period in which little crystallinity is observed with respect to the X-ray and infrared measurements. At a later stage of crystallization, the samples exhibited the orientation of crystallites with the c-axis parallel to the magnetic field.

Magnetic orientation of poly(ethylene-2,6-naphthalate) (PEN) and isotactic polystyrene (iPS) has been reported. The orientation starts to occur during the induction period of isothermal melt crystallization process, i.e. during the initial stage of crystallization process where no crystal growth is yet observed with respect to the wide angle X-ray diffraction. In the case of PEN, the crystallites obtained at later stages of crystallization were aligned with its c-axis parallel to the magnetic field, while in the case of iPS, the crystallites obtained were aligned with its c-axis perpendicular to the magnetic field. X-ray, infrared, and magnetic birefringence measurements indicated that mesophases appearing during the induction period could be responsible for the magnetic orientation of these polymers.

Structures and tensile properties were investigated for magnetically oriented commercial thermotropic liquid crystalline copolyesters, Xydar and Rodrun. The orientation dependence and the magnitude of the tensile properties were similar between these two copolyesters. Comparison was made with the results obtained for the mechanically oriented samples of these copolyesters. It was found that the ultimate tensile strength and the elongation at break obtained for the magnetically oriented samples were different from those obtained for the mechanically oriented samples. Structure analyses conducted by means of polarizing microscope and X-ray diffraction showed that the two different orientation methods provide different structures on macroscopic as well as microscopic levels. The difference in the tensile properties could be attributed to the difference in structures.

A kinetics of the orientation of a commercial liquid crystalline copolyester (60 mol% p-hydroxybenzoic acid/40 mol% ethylene terephthalate) in the magnetic field (6 T) was studied by means of X-ray measurements. The data were analyzed in terms of the domain model and the lattice model simulation. The rates of the magnetic orientation from an initial random state of orientation were found to be of 10−4 to 10−2 s−1 depending on temperatures. The comparison of the results obtained by the domain model and by the simulation suggested that the inter-domain interaction is important to explain the experimental result obtained for the reorientation process.

Elastic moduli and linear coefficients of thermal expansion (CTE) of a random thermotropic liquid crystalline copolyester, oriented in a magnetic field and by mechanical methods were measured in the directions parallel and perpendicular to the orientation direction. The axial elastic modulus of the magnetically oriented film was lower than that of the uniaxially stretched film. The elastic modulus measured in the transverse direction was higher for the magnetically oriented film. In the axial direction, both the mechanically stretched and magnetically oriented films exhibited shrinkage at low temperatures (CTE ≈ -2 · 10−5 K−1) and exhibited expansion at elevated temperatures. In the transverse direction, expansion was observed except for the biaxially stretched film at low temperatures. The magnetically oriented film showed the lowest axial CTE at elevated temperatures.

The melt crystallization process of isotactic polystyrene (i-PS) was studied by means of in situ Fourier transform infrared (FTIR) spectroscopy, with a focus on the conformational changes during the induction period. The spectra obtained during the induction period suggested the occurrence of some ordered structure that is characterized by higher regularity and packing of the helical moieties than observed in the melt. This ordered structure was clearly different from the amorphous structure, and close to the crystal structure. The Avrami analysis indicated that the formation process of the ordered structure at the late stage of the induction period is similar to the growth process of the crystallites after the induction period.