Search

This letter proposes a mobile quad-arm robot: ARMS that unifies wheel-legged tripedal mobility, wheeled mobility, and quad-arm manipulation. The four arms have different mechanics and are designed to be general-purpose arms to enable the wheel-legged hybrid mobilities and manipulation. The three-degree-of-freedom (DOF) front arm has an active wheel, which is used for wheel-legged tripedal walking and wheel driving with passive wheels attached to the torso. The three-DOF rear arms are series elastic arms, which are used for wheel-legged tripedal walking, object grasping, and manipulation. The two-DOF upper arm is used for manipulation only; its position and orientation are determined by coordinating all arms. Each motor is controlled by an angle controller and trajectory modification with angle, angular velocity, angular acceleration, and torque constraints. ARMS was experimentally validated on the basis of the following four tasks: wheel-legged walking, wheel-driving, wheel-driving with grasping, and carrying a bag.

Additional file 8. Forest plot for PROMs in additional analysis.

Japan

Additional file 1. PRISMA NMA Checklist of Items to Include When Reporting A Systematic Review Involving a Network Meta-analysis.

Additional file 5. League tables.

Additional file 4. Assessing confidence in the results of a network meta-analysis.

Additional file 6. Forest plot for the pairwise analysis.

Additional file 1: Figure S1. Binding properties of DS-1594a·succinate. (A) Green sticks represent amino acid residues that form specific interactions (i.e., hydrogen bonds, π-π interactions, and CH-π interactions) with DS-1594a·succinate. (B) The magenta surface shows the solvent-accessible surface calculated from protein atoms within 5 Å from DS-1594a·succinate. DS1594a·succinate and Menin atoms are shown in yellow and green, respectively. The color scheme of the line and stick is the same as that in (A). Figure S2. Induction of differentiation and loss of cKit+ cells by the Menin-MLL1 inhibitor using MLL-AF9–evoked murine AML-like cells. (A) Representative microscopic images of MGG staining of MLL-AF9–evoked murine AML-like cells after 7 days of treatment with DMSO, DS-1594a·HCl (10, 20, 40 nM), or Ara-C (50, 100). (B) Based on the MGG staining images as indicated in (A), the cells were counted and classified into 5 differentiation categories (blast, myelocyte, metamyelocyte, banded neutrophil, neutrophil). (C) Representative images of FCM analysis with the indicated antibodies for MLL-AF9–evoked murine AML-like cells after 7 days of treatment with DMSO, DS-1594a·succinate (10, 20, and 40 nM), or Ara-C (50 and 100 nM). (D) RT‒qPCR was performed in MLL-AF9–evoked murine AML-like cells after treatment with DS-1594a·succinate (10, 20, 40 nM) or Ara-C (50, 100) for 7 days. The expression levels of Kit (Cd117), Itgam (Cd11b), and Ly6g were normalized to that of Actb and compared to those in the DMSO-treated controls (mean ± SD; n=3). (E) FCM analysis with the cKit antibody for MLL-AF9–evoked murine AML-like cells after 4 days of treatment with DMSO or DS-1594a·succinate (1.5, 4.6, 14 and 41 nM). The bars represent the mean ± SD; n=3. MGG, May-Grünwald-Giemsa; AML, acute myeloid leukemia; Ara-C, cytarabine; MLL, mixedlineage leukemia; APC, allophycocyanin; PE, phycoerythrin. Figure S3. Effect of the Menin-MLL1 inhibitor on the induction of CD11b+ differentiation and loss of CD34+/CD38- AML cells in MLL1-r+ AML patient-derived cells in vitro. Patient-derived primary AML cells (AML#8531, NCCHD010, and AML676) were treated for 7 days with DMSO, DS-1594a·succinate, or Ara-C at the indicated concentrations. Representative images of dot plots and histograms in FCM analysis with anti-human CD34/CD38 antibodies (A) and an anti-human CD11b antibody (B) are shown. (C) RT‒qPCR was performed in AML#8531 and AML676 cells after treatment with DS-1594a·succinate (30, 100, 300, nM) or Ara-C (30, 100) for 7 days. The expression levels of CD34 and ITGAM (CD11b) were normalized to that of ACTB and compared to those in the DMSO-treated controls (mean ± SD; n=3). hCD, human CD. Figure S4. Effect of the Menin-MLL1 inhibitor on the induction of differentiation and loss of potential LICs in NPM1c AML patient-derived cells in vitro. Patient-derived primary NPM1c AML cells (AML#7789, AML#7915, AML#7919) were treated for 7 days with the indicated compounds. (A) FCM analysis of CD33+ cells with anti-human CD34 and CD38 antibodies (AML#7789) or viable cells with anti-human CD33 and CD123 antibodies (AML#7915 and AML#7919). (B) FCM analysis of viable cells with an anti-human CD11b antibody. (C) RTqPCR to detect the expression levels of MEIS1 and HOXA9 (mean ± SD; n = 2 [technical replicates]) normalized to those of GAPDH. AML, acute myeloid leukemia; Ara-C, cytarabine; FCM, flow cytometry; hCD, human CD; LIC, leukemia-initiating cell; NPM1c, mutated nucleophosmin 1; PE, phycoerythrin; PerCP, peridinin-chlorophyll protein complex; RT‒qPCR, real-time quantitative PCR. Figure S5. Changes in Menin/MLL1 occupancies in NCCHD010 cells. (A) RNA-seq was performed in MOLM-13 and NCCHD010 cells treated with DS-1594a·succinate for 3 and 7 days, respectively, at the indicated concentrations. The graphs represent the expression levels of the indicated genes compared to those in the DMSO-treated controls (mean ± SD, n=3). (B) ChIP-seq was performed in NCCHD010 cells treated with 500 nM or 5 μM DS-1594a·succinate for 3 days. Normalized coverage tracks of menin, MLL1, H3K79me2, and H3K4me3 ChIP-seq signals (read per million) at selected target genes in NCCHD010 are shown. The peaks around the TSS are shown. Figure S6. Tumor burden in an AML-PDX model (AM7577) treated with the Menin-MLL1 inhibitor. The tumor burdens in the PB, spleens, and BM of AM7577 mice were assessed by the presence of hCD45+ cells at termination (day 35; n = 6 mice per group). AML, acute myeloid leukemia; hCD, human CD; PB, peripheral blood; PDX, patientderived xenograft. Figure S7. In vivo antitumor effect of the Menin-MLL1 inhibitor in the ALL-PDX model (NCCHD007). RTqPCR to assess the mRNA expression levels of human MEIS1, MEF2C, and CDK6 in the bone marrow of NCCHD007 mice 1 day after 28 days of treatment (day 38) with DS1594a·succinate. The expression levels were normalized to human GAPDH mRNA levels (mean ± SD, n = 3). Figure S8. Pharmacokinetics Parameters in Plasma after Single Oral Administration of DS-1594a·succinate to mice. Blood samples were collected at 1, 2, 6, and 24 hours after a single oral administration of DS-1594a·succinate to severe combined immunodeficiency (SCID) mice at 6.25, 12.5, 25, 50, and 100 mg/kg. Values are mean ± standard deviation (n = 3/group). AUC24h, area under the plasma concentration-time curve up to 24 hours; Cmax, maximum plasma concentration; Tmax, time to reach maximum plasma concentration. Figure S9. Hematology in mice treated orally with DS-1594a·succinate for 28 days before a 28-day recovery period. White blood cell count (WBC), neutrophil count (Neutro.), red blood cell count (RBC), hemoglobin concentration (HGB), and platelet count (PLT) were measured in Crl:CD1 (ICR) mice that were orally administered 0 (vehicle control), 30, 100, or 300 mg/kg (DS-1594a·succinate) once daily for 28 consecutive days (end of the dosing period, 10 mice/group). Five animals treated at dose levels of 0 and 300 mg/kg were used to evaluate the reversibility of toxicity during a 28-day recovery period (end of the dosing recovery period, 5 mice/group). Figure S10. The number of the granulocyte/macrophage colony-forming unit (CFU-GM) of CB-CD34+ using MethoCult H4535. The total number of CFU-GM from human cord blood-derived CD34+ cells was counted using microscopy at 12 days post seeding in MethoCult H4535 and treatment with DMSO, DS-1594·HCl or Ara-C. Each circle indicates the CFU-GM number of each plate and bars represent mean value, n = 2. Table S1. Statistics for data collection and phase refinement. Table S2. Antibodies used for FCM in murine MA9 cells. Table S3. Sample types used for FCM in murine MA9 cells. Table S4. Antibodies used for ChIP. Table S5. Antibodies used in FCM analysis of human-derived AML676 and NCCHD010 cells. Table S6. Antibodies used in FCM analysis of human-derived AML#8531, AML#7789, AML#7915, and AML#7919 cells. Table S7. Information on primary patient samples.

Additional file 7. Funnel plots.

論文, Articles

Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein-Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease. SIGNIFICANCE: A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5330/F1.large.jpg.

Background The importance of management of metabolic syndrome (MetS) for risk reduction of cardiovascular disease (CVD) has been recognized worldwide. Because of the comparatively unique characteristics of bodily figure/obesity and incident CVD in Japan, the relevance of MetS on CVD can be still discussed among Japanese people. The present study aimed to review briefly the relationship of MetS with CVD morbidity/mortality among general Japanese people. Methods Population-based prospective cohort studies evaluating the predictive value of MetS on CVD morbidity/mortality via a PubMed search up to 2019 were summarized. Results We identified two studies on morbidity that reported MetS to predict CVD morbidity. We identified three studies on mortality, and these studies showed an increased direction of hazard ratio (HR) of CVD mortality, while one study reported an insignificant prediction of MetS for CVD mortality. In the meta-analysis method, MetS significantly predicted CVD morbidity (HR=1.71 [95% confidence interval=1.34–2.18] in men and HR=1.89 [95% confidence interval=1.45–2.46] in women) as well as CVD mortality (HR=1.68 [95% confidence interval=1.37–2.06] in men and HR=1.73 [95% confidence interval=1.39–2.15] in women). Conclusion Among general Japanese people, MetS can be a positive predictor of CVD morbidity/mortality. Since the studies are limited, more research is needed to establish the findings.

この論文は、科学研究費 (JSPS Kakenhi) 基盤研究 (C) 課題番号 JP-17K02804「日英語ならびに西欧諸語における時制とその関連領域に関する発展的研究」(研究代表者：和田尚明)、基盤研究 (B) 課題番号 JP18H00667「ロマンス諸語におけるテンス・アスペクト・モダリティ・エビデンシャリティの対照研究」(研究代表者：山村ひろみ) の助成をうけて行なわれた研究の成果の一部である。

Anxiety affects respiration, and in turn perturbs the internal environment, although the neuronal systems controlling anxiety-related respiration remain unclear. Recent reports indicate that serotonin（5-HT）neurons in the median raphe nucleus（MRN）enhance anxiety. In the present study, we aimed to clarify the contribution of 5-HT neurons in the MRN to anxiety and respiratory control using mice expressing a channelrhodopsin-2 variant-enhanced yellow fluorescent protein（ChR2 ［C128S］-EYFP; a step-function opsin）in the central 5-HT neurons. We applied an optogenetic method to bigenic mice expressing ChR2［C128S］-EYFP in 5-HT neurons and to monogenic mice without such expression. Photostimulation of free-moving mice was performed using a wireless system through an optical fiber pre-inserted above the MRN, and respiratory variables were measured using whole-body plethysmography. Anxiety was evaluated using an elevated-plus maze test. In the bigenic mice, we confirmed ChR2［C128S］-EYFP expression in tryptophan hydroxylase 2（a brain 5-HT synthase）-positive neurons in the raphe nuclei of the mesopontine, such as the MRN and the dorsal raphe nucleus. Blue light illumination to the MRN of the bigenic mice significantly increased respiratory rate and minute ventilation without affecting tidal volume, and significantly decreased the time spent in the open arms of the elevated plus maze without changing distance traveled, compared with monogenic mice. These results suggest that 5-HT neuron activity in the MRN increases anxiety-like behavior without affecting locomotor activity, enhances respiratory rhythm and minute ventilation without changing tidal volume, and can mimic anxiety-related respiratory responses in humans.

この論文は、科学研究費 (JSPS Kakenhi) 基盤研究 (C) 課題番号 25370422「フランス語および日本語におけるモダリティの発展的研究」(研究代表者：渡邊淳也)、基盤研究 (C) 課題番号 17K02804「日英語ならびに西欧諸語における時制とその関連領域に関する発展的研究」(研究代表者：和田尚明)、基盤研究 (B) 課題番号 18H00667「ロマンス諸語におけるテンス・アスペクト・モダリティ・エビデンシャリティの対照研究」(研究代表者：山村ひろみ) の助成をうけて行なわれた研究の成果の一部である。

Supplemental material, sj-docx-1-tam-10.1177_17588359211009143 for Efficacy and safety of trifluridine/tipiracil plus bevacizumab and trifluridine/tipiracil or regorafenib monotherapy for chemorefractory metastatic colorectal cancer: a retrospective study by Keigo Chida, Daisuke Kotani, Yoshiaki Nakamura, Akihito Kawazoe, Yasutoshi Kuboki, Kohei Shitara, Takashi Kojima, Hiroya Taniguchi, Jun Watanabe, Itaru Endo and Takayuki Yoshino in Therapeutic Advances in Medical Oncology

Jun Watanabe, Kazuhiko Kotani Center for Community Medicine, Jichi Medical University, Shimotsuke-City, JapanCorrespondence: Kazuhiko KotaniCenter for Community Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-City, Tochigi 329-0498, JapanTel +81-285-58-7394Fax +81-285-44-0628Email kazukotani@jichi.ac.jpBackground: The importance of management of metabolic syndrome (MetS) for risk reduction of cardiovascular disease (CVD) has been recognized worldwide. Because of the comparatively unique characteristics of bodily figure/obesity and incident CVD in Japan, the relevance of MetS on CVD can be still discussed among Japanese people. The present study aimed to review briefly the relationship of MetS with CVD morbidity/mortality among general Japanese people.Methods: Population-based prospective cohort studies evaluating the predictive value of MetS on CVD morbidity/mortality via a PubMed search up to 2019 were summarized.Results: We identified two studies on morbidity that reported MetS to predict CVD morbidity. We identified three studies on mortality, and these studies showed an increased direction of hazard ratio (HR) of CVD mortality, while one study reported an insignificant prediction of MetS for CVD mortality. In the meta-analysis method, MetS significantly predicted CVD morbidity (HR=1.71 [95% confidence interval=1.34– 2.18] in men and HR=1.89 [95% confidence interval=1.45– 2.46] in women) as well as CVD mortality (HR=1.68 [95% confidence interval=1.37– 2.06] in men and HR=1.73 [95% confidence interval=1.39– 2.15] in women).Conclusion: Among general Japanese people, MetS can be a positive predictor of CVD morbidity/mortality. Since the studies are limited, more research is needed to establish the findings.Keywords: cardiometabolic health, disease morbidity, disease mortality, obesity

学位の種別: 課程博士, 審査委員会委員 : （主査）東京大学准教授 古田 幹雄, 東京大学教授 小林 俊行, 東京大学教授 河澄 響矢, 東京大学教授 金井 雅彦, 東京大学准教授 入江 慶

Supplemental material, 20191107supplementary_material_1 for High-Density Lipoprotein Cholesterol and Risk of Stroke Subtypes: Jichi Medical School Cohort Study by Jun Watanabe, Eiichi Kakehi, Kazuhiko Kotani, Kazunori Kayaba, Yosikazu Nakamura and Shizukiyo Ishikawa in Asia Pacific Journal of Public Health

第20回宇宙科学シンポジウム (2020年1月8日-9日. 宇宙航空研究開発機構宇宙科学研究所(JAXA)(ISAS)相模原キャンパス), 相模原市, 神奈川県, 20th Space Science Symposium (January 8-9, 2020. Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency(JAXA)(ISAS)Sagamihara Campus), Sagamihara, Kanagawa Japan, 資料番号: SA6000152092, レポート番号: P1.66

We have previously published liquid biopsy for the diagnosis of brain tumors including PCNSL (JCO Precision Oncology, 2019; Leukemia and Lymphoma, 2019) and diffuse midline gliomas (DMG) (Diagnostics, 2021). We used the Maxwell RSC cfDNA extraction kit to extract circulating tumor DNA (ctDNA from) 1 milliliter of cerebrospinal fluid (CSF), and droplet digital PCR to detect MYD88 L265P mutations in PCNSL and H3F3A K27M mutations in DMG. From our initial experience, we were able to detect a high rate of MYD88 mutations in PCNSL, but not H3F3A mutations in DMG. We also observed that higher concentrations of ctDNA were obtained when prompt centrifugation and storage were done after obtaining CSF. Application of liquid biopsy to early detection of relapse and monitoring of treatment relapse are highly anticipated. In cases of PCNSL, we perform liquid biopsy when relapse is suspected on post-contrast MRI. However interestingly, the rate of MYD88 mutations detected is lower than that of newly-diagnosed cases. We would also like to share our experience performing liquid biopsy in conjunction with CSF cytology in brain tumor patients with evidence of leptomeningeal disease. From our initial experience, we would like to discuss the present limitations and future prospects of liquid biopsy in brain tumor patients.

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis. Herein, we developed novel, orally bioavailable EZH1/2 dual inhibitors that strongly and selectively inhibited methyltransferase activity of both EZH2 and EZH1. EZH1/2 dual inhibitors suppressed trimethylation of histone H3 lysine 27 in cells more than EZH2 selective inhibitors. They also showed greater antitumor efficacy than EZH2 selective inhibitor in vitro and in vivo against diffuse large B-cell lymphoma cells harboring gain-of-function mutation in EZH2. A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL-AF9, MLL-AF4, and AML1-ETO. A solid cancer panel assay demonstrated that some cancer cell lines are sensitive to EZH1/2 dual inhibitor in vitro and in vivo. No clear correlation was detected between sensitivity to EZH1/2 dual inhibitor and SWI/SNF mutations, with a few exceptions. Severe toxicity was not seen in rats treated with EZH1/2 dual inhibitor for 14 days at drug levels higher than those used in the antitumor study. Our results indicate the possibility of EZH1/2 dual inhibitors for clinical applications.

Sphincter‐preserving procedures (SPPs) for surgical treatment of low‐lying rectal tumors have advanced considerably. However, their oncological safety for locally advanced low rectal cancer compared with abdominoperineal resection (APR) is contentious. We retrospectively analyzed cohort data of 1500 consecutive patients who underwent elective resection for stage II‐III rectal cancer between 2010 and 2011. Patients with tumors 2‐5 cm from the anal verge and clinical stage T3‐4 were eligible. Primary outcome was 3‐year local recurrence rate, and confounding effects were minimized by propensity score matching. The study involved 794 patients (456 SPPs and 338 APR). Before matching, candidates for APR were more likely to have lower and advanced lesions, whereas SPPs were carried out more often following preoperative treatment, by laparoscopic approach, and at institutions with higher case volume. After matching, 398 patients (199 each for SPPs and APR) were included in the analysis sample. Postoperative morbidity was similar between the SPPs and APR groups (38% vs 39%; RR 0.98, 95% CI 0.77‐1.27). Margin involvement was present in eight patients in the SPPs group (one and seven at the distal and radial margins, respectively) and in 12 patients in the APR group. No difference in 3‐year local recurrence rate was noted between the two groups (11% vs 14%; HR 0.77, 95% CI 0.42‐1.41). In this observational study, comparability was ensured by adjusting for possible confounding factors. Our results suggest that SPPs and APR for locally advanced low rectal cancer have demonstrably equivalent oncological local control.

Let $X$ be a smooth compact manifold with corners which has two embedded boundary hypersurfaces $\partial_0 X , \partial_1 X$, and a fiber bundle $\phi:\partial_0 X \to Y$ is given. By using the method of blowing up, we define a pseudodifferential culculus $\Psi ^* _{\Phi,b} (X)$ generalizing the $\Phi$-calculus of Mazzeo and Melrose and the (small) $b$-calculus of Melrose. We discuss the Fredholm condition of such operators and prove the relative index theorem. And as its application, the index theorem of "non-closed" $\mathbb{Z}/k$ - manifolds is proved.

Tetragenococcus halophilus, a halophilic lactic acid bacterium, is often used as a starter culture in the manufacturing of soy sauce. T. halophilus possesses an arginine deiminase system, which is responsible for the accumulation of citrulline, the main precursor of the potential carcinogen ethyl carbamate. In this study, we generated five derivatives lacking arginine deiminase activity from T. halophilus NBRC 12172 by UV irradiation. Using these derivatives as a fermentation starter prevented arginine deimination in soy sauce. DNA sequence analysis of the derivatives revealed that novel IS4 family insertion sequences, designated ISTeha3, ISTeha4, and ISTeha5, were transposed into the region around the arginine deiminase (arc) operon in the mutants. These insertion sequences contain a single open reading frame encoding a putative transposase and 13- to 15-bp inverted repeats at both termini, which are adjacent to 7- to 9-bp duplications of the target sequence. Investigation of wild strains isolated from soy sauce mash incapable of arginine deimination also indicated that insertion sequences are involved in the disruption of the arginine deiminase system in T. halophilus. IMPORTANCE Insertion sequences play important roles in bacterial evolution and are frequently utilized in mutagenesis systems. However, the intrinsic insertion sequences of tetragenococci are not well characterized. Here, we identified three active insertion sequences of T. halophilus by transposition into the region around the arc operon. This report provides an example of insertion sequence-mediated generation and evolution of T. halophilus and primary information about their characteristics.

Additional file 1: Table S1. Multivariate analysis of cancer mortality with metabolic syndrome by sex, excluding participants

著者人数: 37名, Accepted: 2018-09-10, 資料番号: SA1180349000

著者人数: 83名, Accepted: 2017-07-13, 資料番号: SA1170168000

Object: To investigate the usefulness of ultraviolet-microscopic spectroscopy （UV-MS） of unstained cells by liquid-based cytology （LBC） to objectively differentiate non-cancer from cancer cells. Study Design: Cultured cells were used as the sample cells: 100 non-cancer cells and 200 cancer cells. The sample measurement region was a 166.4-μm2 area in the nuclear region of sample cells. On UV-MS, data of 260, 280, 300, 320, and 340 nm were extracted from the transmittance spectrum of 260-350-nm ultraviolet （UV） wavelengths and analyzed. Result: At a 300-nm UV wavelength, transmittances in non-cancer and cancer cells were 79.7±5.0 and 64.1±5.0%, respectively, being signifi cantly lower in cancer cells （P, 弘前医学. 65, 2014, p.82-94

Enhancer of zests homologous (EZH)1 and its close homolog EZH2 are component of polycomb repressive complex (PRC) 2 protein complex, and play redundant and crucial role for the maintenance of transcriptional repression by tri-methylating histone H3 lysine 27 (H3K27). Hyper tri-methylation of H3K27 has been associated with lymphoma and myeloma progression, suggesting that PRC2 is a therapeutic target for hematological malignancies. Selective EZH2 inhibitors induce compensatory activation of EZH1 which in turn re-activates PRC2 function. We hypothesized that dual inhibition of EZH1 and EZH2 is more effective than selective EZH2 inhibition as anti-tumor therapy. We have developed a novel EZH1 and EZH2 dual inhibitor DS-3201, which simultaneously inhibited the enzymatic activity of EZH1 and EZH2 in nano-molar concentration. DS-3201 showed anti-proliferative effect against various NHL cells, such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and peripheral T-cell lymphoma, with GI50 values less than 100 nM regardless of EZH2 gain-of-function mutations. DS-3201 also induced differentiation of undifferentiated NHL cells with increment of cell lineage specific markers and which induced cell death in vitro. DS-3201 also showed synergistic effect with the standard of care agents for NHL in vitro and in vivo. An open-label phase 1 clinical study was initiated to examine the safety and pharmacokinetics of multiple-dose monotherapy of DS-3201b which is the salt form of DS-3201 in patients with NHL (ClinicalTrials.gov Identifier: NCT02732275). Eighteen patients with relapsed or refractory NHL were enrolled. The patients received oral administration of DS-3201b once daily in a 28-day cycle at dose of 150, 200 and 300 mg. Preliminary efficacy results (D. Maruyama, et al. ASH 2017), showed that the overall response rate was 58.8% (10/17) with 1 complete response and 9 partial responses (PR). Thirteen NHL patients including five follicular lymphoma (FL) and one DLBCL were analyzed for gene mutation status by targeted gene sequencing. EZH2 mutation was detected only in one FL patient, who achieved PR. It was suggested that DS-3201b has clinical activity against NHL, regardless of the mutation status of EZH2. Disclosures Honma: Daiichi Sankyo: Employment. Nosaka:Daiichi Sankyo: Employment. Shiroishi:Daiichi Sankyo: Employment. Takata:Daiichi Sankyo: Employment. Hama:Daiichi Sankyo: Employment. Yamamoto:Daiichi Sankyo RD Novare: Employment. Adachi:Daiichi Sankyo: Employment. Maruyama:Mundipharma International: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Dai-ichi-Sankyo: Honoraria; Bristol-Myers Squibb: Honoraria; Biomedis International: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Dai-Nippon-Sumitomo: Honoraria; Asahi Kasei Pharma: Honoraria; AstraZeneca: Research Funding; Solasia Pharma: Research Funding; Pfizer: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Novartis: Research Funding; Otsuka: Research Funding; Amgen Astellas BioPharma: Research Funding; Astellas Pharma: Research Funding; Abbvie: Research Funding; GlaxoSmithKline: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding. Tobinai:Chugai Pharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Eisai: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SERVIER: Research Funding; Abbvie: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; HUYA Bioscience International: Consultancy, Honoraria. Ishida:Kyowa Hakko Kirin Co.Ltd: Honoraria, Research Funding; Celgene K.K: Honoraria, Research Funding; Bayer AG: Research Funding; Mundiparma K: Honoraria. Kusumoto:Bristol-Myers Squibb: Honoraria, Research Funding; Chugai Pharmaceutical Co. Ltd: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Tsukasaki:Daiich-Sankyo: Consultancy; Ono Pharma: Consultancy; HUYA: Consultancy, Research Funding; Chugai Pharma: Honoraria, Research Funding; Eisai: Research Funding; Celgene: Honoraria; Mundy Pharma: Honoraria; Kyowa-hakko/Kirin: Honoraria; Seattle Genetics: Research Funding. Fujioka:Daiichi Sankyo: Employment. Watanabe:Daiichi Sankyo: Employment. Kanno:Daiichi Sankyo: Employment. Kumazawa:Daiichi Sankyo RD Novare: Employment. Fujitani:Daiichi Sankyo: Employment. Araki:Daiichi Sankyo: Employment. Fujiwara:Daiichi Sankyo: Employment.

To investigate the long-term oncologic outcomes and prognostic factors in patients with obstructive colorectal cancer (CRC) at multiple Japanese institutions.We identified 362 patients diagnosed with obstructive colorectal cancer from January 1, 2002 to December 31, 2012 in Yokohama Clinical Oncology Group's department of gastroenterological surgery. Among them, 234 patients with stage II/III disease who had undergone surgical resection of their primary lesions were analyzed, retrospectively. We report the long-term outcomes, the risk factors for recurrence, and the prognostic factors.The five-year disease free survival and cancer-specific survival were 50.6% and 80.3%, respectively. A multivariate analysis showed the ASA-PS (HR = 2.23, P = 0.026), serum Albumin ≤ 4.0 g/dL (HR = 2.96, P = 0.007), T4 tumor (HR = 2.73, P = 0.002) and R1 resection (HR = 6.56, P = 0.02) to be independent risk factors for recurrence. Furthermore, poorly differentiated cancers (HR = 6.28, P = 0.009), a T4 tumor (HR = 3.46, P = 0.011) and R1 resection (HR = 6.16, P = 0.006) were independent prognostic factors in patients with obstructive CRC.The outcomes of patients with obstructive CRC was poor. T4 tumor and R1 resection were found to be independent prognostic factors for both recurrence and survival in patients with obstructive CRC.

A 59-year-old man was referred to our hospital with right hydronephrosis, which was diagnosed from a medical examination. On imaging studies, he had concentric thickness of the right ureteral wall, and retroperitoneal and mesenteric lymphadenopathy. Urine cytology was negative, and an ureteroscopic biopsy showed no malignancy. We performed laparoscopic biopsy of the retroperitoneal lymphadenopathy, and the histopathological diagnosis was B-cell follicular lymphoma. The patient received four cycles of RCVP (rituximab, cyclophosphamide, vincristine, prednisolone) chemotherapy and four cycles of rituximab monotherapy and then he obtained complete remission. If concentric thickness of the ureteral wall is found, physicians should beawareof thepossibility of malignant lymphoma and should consider laparoscopic biopsy for diagnosis.