Sumitomo Dainippon Pharma Research Articles

High Expression of MEF2D-Fusion Protein Is Caused By Escaping from the Suppression By miRNA and Leads to Suppress Transcriptional Activity of PAX5

We previously discovered new fusion genes, MEF2D-BCL9 and MEF2D-HNRNPUL1, in 9% of adolescent and young adult B-cell acute lymphoblastic leukemia (ALL; Yasuda T, et al. , Nature Genetics, 2016;48:569-574). Vector driving expression of MEF2D-fusion protein was markedly higher than the expression of wild-type MEF2D (MEF2D W) protein driven by the same expression vector system; however, the mechanism and significance of the high-expression have been yet to be clarified.We first confirmed fusion specific MEF2D high expression was occurred in MEF2D fusion-positive ALL cell lines, Kasumi-7 and Kasumi-9. Protein half-life and the effect of proteasome inhibitor on protein expression were not significantly different between MEF2D W and MEF2D-fusion, suggesting that stability of protein was not different between them. We speculated that MEF2D fusion gene lost the miRNA target that existed in C-terminal half of MEF2D mRNA and that the high-expression of MEF2D fusion protein was caused by escaping from the suppression by miRNA (Figure A). In order to investigate this speculation, we made several expression vectors of MEF2D that express same partial MEF2D protein but transcript different length of mRNA. That is, we introduced a mutation substituting stop codon for D336, the breakpoint of MEF2D-HNRNPUL1 fusion protein, into the expression vector of wild-type MEF2D and designated it as MEF2D (full D336Stop). We deleted C-terminal legion from it with various lengths (Figure B). The protein expression level of MEF2D (1-335) from MEF2D (full D336Stop) vector was similar to that of MEF2D W; however, the protein expression level was markedly increased when DNA region coding amino acid (aa) 377-418 was deleted from the expression vector (Figure C), indicating that protein expression of MEF2D (1-335) was down regulated by miRNA targeting mRNA coding aa 377-418. We identified a candidate of responsible miRNA by database search. Transfection of miRNA mimic of the candidate miRNA decreased the protein expression of MEF2D W but not that of MEF2D fusion. Introduction of mutation at the binding site of the candidate miRNA increased the protein expression of MEF2D W. We examined the effect of MEF2D fusion protein on transcriptional activity of various B cell differentiation regulators and found that MEF2D-fusion protein suppressed transcriptional activity of PAX5 in luciferase assays in dose-dependent manner and that MEF2D W protein did not significantly affect it. These results suggested that the high-expression of MEF2D fusion protein impaired B cell differentiation through the inhibition of PAX5 function. This is the first report that a mutation of a coding gene causes high expression of the protein coded by the gene through escape from suppression by miRNA. These results shed a new insight into the mechanism of leukemia development by MEF2D fusion gene and pathological significance of miRNA-related disorder. [Display omitted] DisclosuresNaoe:Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Nippon Boehringer Ingelheim Co.: Honoraria, Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Dainippon Sumitomo Pharma Co.,LTD.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding. Kiyoi:Bristol-Myers Squibb: Honoraria, Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Meiji Seika Pharma Co.,Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; MSD K.K.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; JCR Pharmaceuticals Co.,Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; ONO Pharmaceutical Co., Ltd.: Research Funding; Phizer Japan Inc.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding.

1086-P: A Retrospective Nationwide Surveillance on the First-Line Antidiabetic Medication for the Patients with Type 2 Diabetes in Japan

Background: To investigate the national trend in prescription of first-line non-insulin antidiabetic agents and the annual total medical costs since the first prescription in Japanese patients with type 2 diabetes. Materials and Methods: Using the National Database of Health Insurance Claims and Specific Health Check-ups of Japan (NDB), we calculated the proportion of each antidiabetic drug from fiscal year (FY) 2014 to 2017 and determined factors associated with drug selection in multivariable logistic regression analyses. The total medical costs (TMCs) in the first year after starting the drugs were calculated and factors associated with the costs were also determined. Results: Among 1,136,723 newly-prescribed patients, dipeptidyl peptidase-4 inhibitors (DPP4i) were most prescribed (65.1%) followed by biguanides (15.9%) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) (7.6%). SGLT2i use increased markedly, as was biguanide gradually increased and other drug use decreased during the study period. Biguanides were not prescribed at all in 38.2% of non-certified facilities by the Japan Diabetes Society. TMCs [adjusted mean, 95% CI] were lowest in biguanides [$4638, 4591-4686] followed by thiazolidinediones [$4670, 4546-4794], moderate in SGLT2i [$5383, 5297-5468] and DPP4i [$5583, 5550-5617], highest in glucagon-like peptide 1 receptor agonist [$8596, 7532-9661] after adjusting for covariates including age and comorbidities. FY, age, gender, type of insurance, facility, number of beds, and comorbidities were associated with drug choice and medical costs in the model. There was wide regional variation in initial choice of antidiabetic drugs but not in the TMCs. Conclusions: Unlike in Europe and the US, DPP4i stands as a first-line treatment in Japan. The wide variation in the drug choice by facility and prefecture may suggest the need to create a new strategy such as algorithms that facilitate appropriate drug selection in Japan. Disclosure R. Bouchi: None. T. Sugiyama: None. A. Goto: None. K. Imai: None. N. Ihana-sugiyama: None. M. Ohsugi: Other Relationship; Self; Kyowa Kirin Co., Ltd., Research Support; Self; Abbott Japan Co., Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Novartis Pharma K. K., Novo Nordisk Pharma Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd. T. Yamauchi: Other Relationship; Self; Abbott Japan LLC, Astellas Pharma Inc., AstraZeneca K. K., Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyorin Pharmaceutical Company, Limited, Kyowa Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Research Support; Self; Aero Switch, Asahi Mutual Life Insurance Company, Bayer Yakuhin, Ltd., Mitsubishi Corporation Life Sciences Limited, NIPRO Medical Corporation, NTT Docomo Inc., Shionogi & Co., Ltd., Tosoh Corporation. T. Kadowaki: Other Relationship; Self; Asahi Mutual Life Insurance Company, MSD Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd. K. Ueki: Advisory Panel; Self; Abbott Japan Co., Ltd., AstraZeneca K. K., Bayer Yakuhin, Ltd., Novo Nordisk Pharma Ltd., Poxel SA, Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca K. K., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Health and Labour Sciences Research Grants (20FA1016)

780-P: Improved Mitochondrial Function by Luseogliflozin Prevents Pancreatic Beta-Cell Damage

We previously showed a sodium glucose co-transporter 2 (SGLT2) inhibitor, luseogliflozin, increased beta cell mass and improved beta cell function in db/db mice, but the mechanism has remained unclear. The aim of this study is to investigate the mechanism of favorable effects of luseogliflozin on beta cells. Six-week-old db/db mice were fed to standard chow (control group) or standard chow containing 0.01% luseogliflozin (luseo group) for 4 weeks. DNA microarray analysis, real-time PCR analysis, measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation, and metabolome analysis were performed using isolated islets. Immunohistochemistry and electron microscopy were performed using pancreatic tissues. DNA microarray and real-time PCR analysis showed gene expressions of solute carrier family 2 member 2 (Slc2a2) related to glucose uptake, pyruvate carboxylase (Pcx) and enzymes related to the tricarboxylic acid (TCA) cycle, and cytochrome c oxidase subunit 6A2 (Cox6a2) related to electron transport chain were upregulated in the luseo group. The luseo group had a higher mitochondrial complex II-linked oxidative phosphorylation capacity, and had a lower mitochondrial ROS generation compared with the control group. Electron microscopy showed mitochondrial swelling in the control group, while the mitochondrial size was normally maintained in the luseo group. Immunohistochemistry showed the proportion of Nkx6.1 positive cells/beta cells was significantly higher in the luseo group compared with the control group (89.8 ± 1.8% vs. 75.3 ± 3.5%, P < 0.01). In metabolome analysis, the metabolites in the TCA cycle were greater in the luseo group compared with the control group. Relief of glucotoxicity by luseogliflozin may reduce mitochondrial ROS generation and elevate Nkx6.1 expression related to beta cell proliferation. The elevated expression of Nkx6.1 could improve glucose metabolism in the TCA cycle, resulting in protection of beta cells. Disclosure Y. Yamauchi: None. K. Cho: None. T. Anzai: None. S. Tanaka: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Novo Nordisk, Sanofi, Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Speaker’s Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. H. Miyoshi: Research Support; Self; Abbott Japan Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Speaker’s Bureau; Self; Astellas Pharma Inc., Eli Lilly Japan K. K., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd. T. Atsumi: Research Support; Self; Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly Japan K. K., Gilead Sciences, Inc., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., UCB Japan Co. Ltd., Speaker’s Bureau; Self; AbbVie Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Takeda Pharmaceutical Co., UCB Japan Co. Ltd. A. Nakamura: Research Support; Self; Boehringer Ingelheim International GmbH, Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Taisho Pharmaceutical Co., Ltd. T. Yokota: None. K. Takahashi: None. S. Kawata: None. K. Tsuchida: None. K. Omori: None. H. Nomoto: None. H. Kameda: None.

205-OR: Docosahexaenoic Acid Suppresses Oxidative Stress-Induced Autophagy and Cell Death through the AMPK-Dependent Signaling Pathway in Immortalized Adult Rat Schwann (IFRS1) Cells

Autophagy is a catabolic process that removes damaged intracellular organelles components by lysosomal degradation, but it is also activated by oxidative stress. We previously reported that the docosahexaenoic acid (DHA) suppressed oxidative stress-induced autophagy and cell death in immortalized adult rat Schwann (IFRS1) cells. However, the detailed mechanism has not been clarified yet. Therefore, we aimed to elucidate the intracellular signal transduction pathway by which DHA suppresses oxidative stress-induced autophagy in IFRS1 cells. Treatment with tert-butyl hydroperoxide (tBHP) for 3 hours decreased cell viability measured by MTT assay in IFRS1 cells, while pretreatment with 10 μM DHA for 12 hours significantly protected tBHP-induced cytotoxicity. The signal transduction of autophagy was assessed by immunoblotting of LC3, p62, AMP-activated protein kinase (AMPK) phosphorylation and UNC51-like kinase (ULK1) phosphorylation in IFRS1 cells. 50 μM tBHP increased the LC3-II/LC3-I ratio, and AMPK phosphorylation, whereas tBHP decreased the p62 protein expression, indicating that autophagy was induced by tBHP. Pretreatment with 10 μM DHA for 12 hours significantly decreased the LC3-II/LC3-I ratio and AMPK phosphorylation that were increased by tBHP, whereas DHA increased the p62 protein expression that was decreased by tBHP. p70S6Kinase and 4E-BP phosphorylation was not changed either by tBHP or by DHA. Autophagosome and autolysosome were induced by 50 μM tBHP in IFRS1 cells, as demonstrated by DAPRed and DALGreen staining. DHA pretreatment significantly reduced the production of tBHP-induced autophagosome, but suppression of autolysosome was partial. These results suggest that DHA may prevent against diabetic neuropathy by attenuating oxidative stress-induced autophagy and cell death through the AMPK-dependent signaling pathway in Schwann cells. Disclosure Y. Tatsumi: Research Support; Self; Daiichi Sankyo, Johnson & Johnson, Kyowa Kirin Co., Ltd., Lilly Diabetes, MSD K. K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. J. Nakamura: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Japan Tobacco Inc., Novartis Pharma K. K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Novartis Pharma K. K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. K. Sango: None. K. Kato: None. A. Kato: None. N. Niimi: None. H. Yako: None. T. Himeno: None. M. Kondo: None. S. Tsunekawa: None. Y. Kato: None. H. Kamiya: Speaker’s Bureau; Self; Eli Lilly Japan K. K., MDS Co., Ltd., Novartis Pharma K. K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd. Funding Grant-in-Aid for Scientific Research (18K06763)

7-LB: Lowering of Blood Pressure and Pulse Rate by Switching from DPP-4 Inhibitor to Luseogliflozin in Patients with Type 2 Diabetes and Hypertension: A Multicenter, Prospective, Randomized, Open-Label, Parallel-Group Comparison Trial

Objective: Sodium-glucose cotransporter-2 inhibitor (SGLT2i) treatment had the effect of reducing blood pressure (BP) and cardiovascular events in recent mega-scale trials, but the effects on BP circadian rhythm remained unclear. The present study aimed to determine the nocturnal antihypertensive effect of SGLT2i compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) in patients with type 2 diabetes and hypertension. Research Design and Methods: In this randomized, open-label, parallel-group trial, patients treated with DPP-4i were either switched to luseogliflozin 2.5 mg/day (Luseo group; n=30) or continued DPP-4i (DPP-4i group; n=26). The patients undertook 24-h ambulatory BP monitoring before and 8 weeks after the group allocation. The primary endpoint was mean change in nighttime systolic BP (SBP). Results: Changes in both nighttime and daytime SBP were significantly reduced in the Luseo group compared with the DPP-4i group (nighttime, −4.0±11.4 vs. 3.6±10.7 mmHg, P=0.01; daytime, −4.4±10.9 vs. 3.7±11.9 mmHg, P=0.01). Similarly, nighttime pulse rate (PR) was significantly reduced in the Luseo group compared with the DPP-4i group (−2.0±4.8 vs. 0.9±4.8 bpm, P=0.03). Abnormal BP circadian rhythms (non-dipper and riser types) were significantly decreased in the Luseo group (56.7% to 36.6%, P<0.05). Conclusions: Switching from DPP-4i to luseogliflozin decreased not only daytime but also nighttime SBP and PR, and improved BP circadian rhythm. These improvements could be some of the factors involved in the cardiovascular event suppression observed with SGLT2i therapy. Disclosure R. Hashimoto-kameda: None. K. Cho: None. H. Nomoto: None. A. Nakamura: Research Support; Self; Boehringer Ingelheim International GmbH, Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Taisho Pharmaceutical Co., Ltd. K. Omori: None. S. Kawata: None. H. Kameda: None. T. Atsumi: Research Support; Self; Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly Japan K. K., Gilead Sciences, Inc., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., UCB Japan Co. Ltd., Speaker’s Bureau; Self; AbbVie Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Takeda Pharmaceutical Co., UCB Japan Co. Ltd. H. Miyoshi: Research Support; Self; Abbott Japan Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Speaker’s Bureau; Self; Astellas Pharma Inc., Eli Lilly Japan K. K., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd. Funding Taisho Pharmaceutical Co., Ltd.

940-P: Prediction of Neurocognitive Disability with Magnitudes of Insulin Resistance and Glucagon-Like Peptide-1 Secretion in Offspring from Mother with Diabetes

Diabetes during pregnancy has been linked with an increased risk of developing metabolic disorders and behavioral abnormalities in the offspring. However, the correlation between those two phenotypes in offspring from mother with diabetes (OMD) has not been tested. We therefore examined the correlation between motor skill learning and glucose tolerance, including glucagon-like peptide-1 (GLP-1) secretion in OMD. ICR female mice received intraperitoneal injection (i.p.) of 150mg/kg streptozotocin at six weeks old. Control female was administered with the vehicle. Those animals showed over 250mg/dL glucose level at 14 days post injection. Mating was done with normal male and all of pups were born in term. Motor skill learning was tested on accelerated rotarod at postnatal 30 days (P30). A learning index was calculated for each animal by averaging the difference in terminal speed when the mouse fall from the rotor rod. Motor learning is impaired in OMD (P =0.0035). Following the behavior test, insulin tolerance test, oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT) were performed. Although the weight of OMD is similar to that of control animals at P21, it was significantly increased after P60 (P <0.0001). The glucose level in the plasma of mice is significantly increased in IPGTT (15, 30min post glucose i.p. injection, p <0.0001) at P60. OMD show higher homeostasis model assessment of insulin resistance (OMD 0.93 vs. control 0.84), and reduced secretion of active GLP-1 (aGLP-1) (OMD 6.70 ng/mL vs. control 8.02 ng /mL) in OGTT. Notably, poor learners of motor skill show significantly lower aGLP-1 secretion than the good learners (P =0.0360). Furthermore, in OMD, neuronal morphology was abnormal in the motor cortex that controls the motor skill learning. These results demonstrate that insulin resistance and the aGLP-1 secretion serve as predictors of motor skill learning deficiencies in OMD. Disclosure H. Iwasaki: None. K. Hashimoto-torii: None. M. Odawara: Speaker’s Bureau; Self; Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kyowa Kirin Co., Ltd., MSD Corporation, Novartis AG, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. R. Suzuki: Research Support; Self; Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Speaker’s Bureau; Self; MSD K. K., Novartis Pharma K. K., Novo Nordisk Pharma Ltd., Sanofi K. K., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. J. Sasaki: None. K. Sugai: None. M. Ito: None. K. Ishii: None. M. Aierken: None. G. Li: None. H. Suwanai: None. M. Torii: None.

29-OR: Regulatory Loop of IR Signaling for Adipocyte Mitochondrial Homeostasis

Insulin and IGF1 signaling initiate Tyr phosphorylation of IR/IGF1R and adaptor IRSs, leading to Ser/Thr phosphorylation of PI3K/AKT and MAPK/ERK pathways essential for the maintenance of brown and white adipose tissues (BAT and WAT). Lack of insulin-signaling in adipose tissues caused metabolic disease in mice with hyperglycemia, hyperlipidemia, and fatty liver, but the mice recovered adipose tissues by regenerating adipocytes. We addressed the mechanism of how adipose tissues regenerate using adipocyte-specific and inducible IR/IGF1R knockout mice (Ai-DKO). We identified a reduction of protein phosphatase protector, α4, which can regulate Ser/Thr phosphorylation of down-stream insulin signaling. shRNA-mediated α4 knockdown (KD) in BAT affected not only insulin-stimulated down-stream Ser/Thr phosphorylation of AKT (S473) but also affected up-stream Tyr phosphorylation of IRβ (Y1162/1163) and IRS1 (Y612). Proteomics analysis of α4-binding molecule identified Y-box protein 1 (YBX1), which functions as a transcription factor for Tyr phosphatase PTP1B. We observed increased PTP1B expression in α4-KO preadipocytes. As the impact of α4 in vivo, inducible adipocyte-specific α4 KO (Ai-α4 KO) mice with tamoxifen-inducible Cre-ERT2 transgene showed cold intolerance, diabetes, ectopic lipid accumulation in the liver, and pancreatic islet hyperplasia, with an increase of C18: 0-ceramide in WAT and BAT. RNA-seq showed a marked reduction of genes associated with mitochondrial fatty acid oxidation and the increases in inflammatory cytokine pathways in Ai-α4 KO WAT and BAT, implicating the cause of fat tissue loss was the increased adipocyte apoptosis. The α4 to PTP1B loop is critical for fat tissue maintenance by regulating IR tyrosine phosphorylation. Disclosure M. Sakaguchi: None. S. Okagawa: None. Y. Okubo: None. K. Fukuda: None. M. Igata: None. J. Kawashima: None. T. Kondo: None. E. Araki: Other Relationship; Self; Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca K. K., Kowa Company, Ltd. Funding Japan Society for the Promotion of Science; Merck Sharp & Dohme Corp; Takeda Foundation

1090-P: Diabetes in Japanese COVID-19 Patients as the Primary Factor of Accelerated Progression to Severe State

During the COVID-19 pandemic, Japanese victims number less than in other countries, perhaps due to gene specifics, aspects of Japanese lifestyle and coagulation system characteristics typically less potent in Japanese than in Caucasians. The Osaka prefectural government stratified patients into mild, moderate and severe, distributing them amongst various alternative accommodation to relieve overburdened hospitals. Hospitalized patients were managed based on national government guidelines. Focusing on moderate patients, i.e., whose oxygen saturation levels were favorable even if presenting characteristics in computed tomography, we conducted a retrospective analysis in type 2 diabetes (T2D) patients compared with a control. Of a study total of 102 patients (male 51%, aged 62.2±16.0, BMI 27.6±5.2), 49% were T2D patients (aged 71.2±13.8, A1c 6.8±1.3%, BMI 24.5±5.2). Twenty-five patients (24.5%) moved to the severe classification. Eighteen patients (17.6%) (aged 74.8±8.6, A1c 6.9±1.0%, BMI 24.3±2.5), of whom 88.9% had T2D (aged 76.1±10.2, A1c 6.7±1.1%, BMI 23.8±10.2), were ventilated and transferred to another hospital for advanced treatment. Seven patients (6.9%), of whom 71.4% had T2D, died (aged 85±3.4) after ventilation was declined by the families due to advanced age and dementia. One scleroderma patient on home oxygen therapy for intestinal pneumonia died of sudden respiratory failure. Twenty-five diabetes patients (24.5%) improved. No significant correlation exists between hypertension, body mass index, lung disease, renal failure and receiving insulin therapy. In our study, 88% of moderate patients moving to the severe classification had T2D. In Japanese, diabetes may constitute a much larger risk factor than those factors identified in other countries in the evolution of COVID-19 patients from the moderate to severe classifications. A more comprehensive study is needed. BMI: body mass index, A1c: hemoglobin A1c. Disclosure S. Kaneko: Advisory Panel; Self; Novo Nordisk Pharma Ltd., Consultant; Self; Novo Nordisk Pharma Ltd., Research Support; Self; Eli Lilly Japan K. K., Novo Nordisk Pharma Ltd., Speaker’s Bureau; Self; AstraZeneca, Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Sumitomo Dainippon Pharma Co., Ltd. H. Kita: None. K. Motohashi: None. S. Tokumoto: None. U. Yoko: None. H. Eguchi: None. I. Tsunematsu: None.

794-P: Predictors of Hemoglobin (Hb) and Its Changes Focusing on Anemia and Polycythemia after Administration of the SGLT2 Inhibitor Tofogliflozin

SGLT2 inhibitors (SGLT2is) increase hematocrit (Ht) and Hb, which may contribute to correcting anemia but also might cause secondary polycythemia. We investigated predictors of Hb after short- and long-term therapy with tofogliflozin (TOFO), a SGLT2i, and explored its impact on Hb in relation to anemia and polycythemia in type 2 diabetes mellitus (T2DM). Analyzed were 774 T2DM patients (66% male) who received TOFO for 52 weeks in two phase 3 studies. Mean baseline characteristics were age 59 y, HbA1c 8%, BMI 26 kg/m2, hemoglobin 15 g/dL and eGFR 84 mL/min/1.73m2. Participants were divided into the Anemia group (baseline Hb <13 g/dL in men and <12 g/dL in women, mean baseline Hb 11.8 g/dL) and Polycythemia group (>16.5 g/dL in men and >16 g/dL in women, mean baseline Hb 17.2 g/dL). Paired t-tests analyzed differences from baseline to weeks 4 and 52. Generalized linear model explored predictors of Hb at weeks 4 and 52. Correlation analysis was performed by Spearman’s product-moment correlation coefficients. Hb was significantly increased at week 4 [mean, +0.14g/dL*; *p<0.05 vs. baseline] and week 52 (+0.34g/dL*). Higher baseline brain natriuretic peptide and lower Ht and triglycerides (TG) were independently correlated with greater increases in Hb at week 4. Lower baseline Hb and TG were significantly correlated with greater increases in Hb at week 52. Higher baseline TG levels and proportion of fatty liver as a comorbidity were observed with higher baseline Hb values. Hb had significantly changed at week 52 in Anemia (+0.94*) and Polythycemia groups (-0.29*). Change in Hb was significantly correlated with change in TG at week 52 (Rho=0.42, p<0.05) in Polycythemia but not Anemia. Increased Hb after short-term TOFO therapy may be due to hemoconcentration while Hb may be corrected according to baseline Hb levels after long-term TOFO therapy. Lower TG in relation to improved fatty liver may be related to correction of higher Hb levels. Disclosure Y. Matsubayashi: None. A. Yoshida: Employee; Self; Kowa Company, Ltd. H. Suganami: Employee; Self; Kowa Company, Ltd. K. Kaku: Advisory Panel; Self; Novo Nordisk Pharma Ltd., Consultant; Self; Sanwa Kagaku Kenkyusho, Research Support; Self; Taisho Pharmaceutical Co., Ltd., Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.

100-OR: ADA Presidents’ Select Abstract: Efficacy and Safety of Once-Weekly Tirzepatide, a Dual GIP/GLP-1 Receptor Agonist vs. Placebo as Monotherapy in People with Type 2 Diabetes (SURPASS-1)

Tirzepatide (TZP) is a novel dual GIP/GLP-1 receptor agonist in development for type 2 diabetes (T2D). Efficacy and safety of TZP vs. placebo (PBO) was assessed in people with T2D inadequately controlled with diet and exercise alone. In this double-blind, PBO-controlled, 40-wk Phase 3 study, people with T2D (N=478; mean baseline [BL] HbA1c 7.94%; age 54.1 y; T2D duration 4.7 y; BMI 31.9 kg/m2) were randomized (1:1:1:1) to TZP (5, 10, 15 mg) or PBO. Primary efficacy measure was mean change in HbA1c from BL at 40 wk. Secondary measures were mean change in fasting serum glucose (FSG) and body weight (BW) and proportion achieving HbA1c and BW goals. TZP 5, 10 and 15 mg were superior to PBO in mean change in HbA1c at 40 wk (LSM treatment difference [95% CI]: -1.91% [-2.18, -1.63], -1.93% [-2.21, -1.65], -2.11% [-2.39, -1.83]; p In conclusion, TZP as T2D monotherapy demonstrated robust clinically meaningful reductions in HbA1c and BW without hypoglycemia (BG Disclosure J. Rosenstock: Board Member; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Consultant; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Research Support; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Genentech, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics, Sanofi. C. H. Wysham: Other Relationship; Self; Abbott Laboratories, American Diabetes Association, Endocrine Society, Medscape Education, Novo Nordisk, Sanofi-Aventis, Research Support; Self; Eli Lilly and Company, Mylan N. V., Mylan N. V., Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. S. Kaneko: Advisory Panel; Self; Novo Nordisk Pharma Ltd., Consultant; Self; Novo Nordisk Pharma Ltd., Research Support; Self; Eli Lilly Japan K. K., Novo Nordisk Pharma Ltd., Speaker’s Bureau; Self; AstraZeneca, Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Sumitomo Dainippon Pharma Co., Ltd. C. Lee: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. L. Fernandez lando: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. H. Mao: Employee; Self; Eli Lilly and Company. X. Cui: Employee; Self; Eli Lilly and Company. V. Thieu: None. Funding Eli Lilly and Company

80-LB: Tirzepatide, a Dual GIP/GLP-1 Receptor Agonist, Is Effective and Safe When Added to Basal Insulin for Treatment of Type 2 Diabetes (SURPASS-5)

Tirzepatide (TZP) is a novel dual GIP/GLP-1 receptor agonist in development for type 2 diabetes (T2D). Efficacy and safety of TZP vs. placebo (PBO) was assessed in people with T2D as an add-on to titrated insulin glargine with or without metformin. In this double-blind, PBO-controlled, 40-wk Phase 3 study, 475 people with T2D (mean baseline [BL] age 60.6 y; T2D duration 13.3 y; HbA1c 8.31%; BMI 33.4 kg/m2) were randomized (1:1:1:1) to TZP (5 mg, 10 mg, 15 mg) or PBO, as an add-on to their existing therapy. Primary efficacy measure was mean change in HbA1c from BL at 40 wk. Secondary measures included change in fasting serum glucose (FSG) and body weight (BW), and proportion of people achieving HbA1c and BW loss goals. All 3 TZP doses were superior to PBO in change from BL in HbA1c, FSG, BW, and percentage patients achieving all HbA1c and BW loss targets at 40 wk (Table). TZP was generally well tolerated and the most common AEs were gastrointestinal (diarrhea, nausea, and vomiting) and mild to moderate in severity. Level 2 hypoglycemia incidence ( Disclosure D. Dahl: Research Support; Self; Afimmune Limited, AstraZeneca, Eli Lilly and Company, Novartis AG, Novo Nordisk. Y. Onishi: Speaker’s Bureau; Self; Daiichi Sankyo Company, Limited, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. P. Norwood: Other Relationship; Self; Eli Lilly and Company, Research Support; Self; Eli Lilly and Company. R. Huh: None. H. Patel: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. A. Rodriguez: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company

Exscientia raises $225 million more

Exscientia, a specialist in artificial intelligence (AI) for drug discovery with its own drug pipeline, has closed a $225 million financing round led by SoftBank Vision Fund 2 with investment from Novo Holdings. Exscientia received an additional $300 million equity commitment from SoftBank. The company has advanced two AI-designed drug candidates into development, including a therapy for obsessive-compulsive disorder developed with Sumitomo Dainippon Pharma .

Bipolar affective disorder

Abstract BodyAbstract: Biomarkers for diagnosis and treatment of Bipolar Disorder: hope or hype? Professor Allan Young, Centre for Affective Disorders, IoPPN, KCL London, SE5 8AF. allan.young@kcl.ac.uk The use of “biomarkers” (biological markers) in basic and clinical research as well as in clinical practice has become so commonplace in many areas of medicine that their presence as primary endpoints in clinical trials is now widely accepted. In clinical disciplines where specific biomarkers have been well characterized and repeatedly shown to correctly predict relevant clinical outcomes across a variety of treatments and populations, this use is entirely justified and appropriate. However, the validity of biomarkers in most psychiatric disorders continues to be evaluated. This lecture will review the current conceptual status of biomarkers as clinical and diagnostic tools for bipolar disorder and as surrogate endpoints in clinical research in bipolar disorder. The conceptual background in terms of current diagnostic categories and research domain criteria will be discussed and the various approaches with putative value (e.g., brain imaging, genetics, and neuroendocrinology) reviewed (1, 2). The lecture will end with a discussion of approaches to evaluating biomarkers of lithium response (3).ReferencesWise et al, Mol Psychiatry. 2016 May 24. doi: 10.1038/mp.2016.72. [Epub ahead of print]; Young AH. Harv Rev Psychiatry. 2014 Nov-Dec;22(6):331–3 Bellivier F, Young AH, et al, Bipolar Disord. 2020 Oct 23. doi: 10.1111/bdi.13023. Online ahead of print.DisclosurePaid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS Principal Inve

Drug Repurposing Patent Applications October-December 2020.

Drug Repurposing Patent Applications October-December 2020.

Sodium-Glucose Cotransporter 2 Inhibitor Versus Sulfonylurea in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized, Open-Label Trial Study

Background: Nonalcoholic fatty liver disease (NAFLD) is a liver phenotype of type 2 diabetes and obesity. Currently, the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas in liver pathology and hepatic gene expression profiles for type 2 diabetes with NAFLD are unknown. Methods: We conducted a 48-week, randomized, open-label, parallel-group trial involving patients with biopsy-confirmed NAFLD. A total of 40 patients were randomly assigned to receive once-daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary endpoint was an improvement in histologic scores of NAFLD. The secondary endpoints were the changes of liver enzymes, metabolic markers, and hepatic gene expression profiles. Findings: All histologic variables: steatosis (65%, P=0.001), hepatocellular ballooning (55%, P=0.002), and lobular inflammation (50%, P=0.003) were improved in the tofogliflozin group, whereas only hepatocellular ballooning was improved in the glimepiride group (25%, P=0.025). Fibrosis scores improved in the tofogliflozin group (60%, P=0.001), whereas the change from baseline did not differ significantly between the groups (P=0.172). Gene expression profiling revealed tofogliflozin accelerated the catabolism of fat and protein that could be utilized for gluconeogenesis. Histological changes in the liver were correlated with substantial improvement of inflammation and fibrosis. Interpretation: Tofogliflozin led to liver histologic and metabolic improvement in patients with type 2 diabetes and NAFLD. The improvements were well supported by the hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors. Clinical Trial Registration Details: This trial is registered with ClinicalTrials.gov, number NCT02649465 (January 7, 2016) and Japan Registry of Clinical Trials; jRCTs041180132 from UMIN 000020544 (January 13, 2016). Funding Information: This work was supported, in part, by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science (grant number 19K08975) and by research grants from Kowa Company Ltd. Declaration of Interests: TTakamura received research grants from Kowa Company Ltd., Mitsubishi Tanabe Pharma Corp., Taisyo Pharma Co., Astellas, Novo Nordisk, Ono Pharmaceutical Co. Ltd., Takeda, Sanwa Kagaku Kenkyusho Co., Ltd., and Life scan Japan. SK received research grants from Takeda, Mitsubishi Tanabe Pharma Corp., EA Pharma Co., Ltd., AbbVie Inc., Eizai Co., Ltd., SANOFI, ZEON MEDICAL INC., ZERIA, Boston Scientific Co., Mylan, TSUMURA, Kyowa Kirin Co., Ltd., Mochida Pharma Co., Ltd., Otsuka Pharma Co., Ltd., Sumitomo Dainippon Pharma, TAIHO PHARMA, Chugai Pharma. Co., Ltd., Lilly, Boehringer Ingelheim, NIHON Pharma. Co., Ltd., and Bristol Myers Squibb. TTakamura and YT received consulting fees from Kowa Company Ltd. TTakamura received lecture fees from MSD, Sumitomo Dainippon Pharma, Mitsubishi Tanabe Pharma Corp. SK received lecture fees from MSD, Sumitomo Dainippon Pharma, AbbVie Inc., EA Pharma Co., Ltd., Eizai Co., Ltd., TAIHO PHARMA, Ono Pharma. Co., Ltd., Takeda and BAYER. EM received lecture fees from MSD, AbbVie Inc., Chugai Pharma. Co., Ltd., EA Pharma Co., Ltd., Bristol Myers Squibb, Ono Pharma. Co., Ltd., Daiichi-Sankyo, and Taisyo Pharma Co. TY received lecture fees from MSD, Sumitomo Dainippon Pharma, AbbVie Inc., Chugai Pharma. Co., Ltd., Eizai Co., Ltd., TAIHO PHARMA, Bristol Myers Squibb, Takeda, BAYER, and Lilly. YT received lecture fees from Sumitomo Dainippon Pharma. YN received lecture fees from Kyowa Kirin Co., Ltd. NI received lecture fees from Miyarisan Pharma. Co., Ltd. MH, KH, YK, NT, HT, TTanaka, HG, KA, and HN have nothing to disclose. Ethics Approval Statement: The institutional review board of each participating institution approved the study protocol in compliance with the Declaration of Helsinki and current legal regulations in Japan. All procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national) and the Helsinki Declaration of 1964, as revised in 2013. The study was conducted with the approval of the Certified Review Board, Kanazawa University, Ishikawa, Japan, by the guidelines of the Declaration of Helsinki (2018-020, CRB4180005, November 11, 2015). Written informed consent was obtained from all of the subjects before enrollment in the study.

Drug Discovery Research for Sumitomo Dainippon Pharma Co., Ltd. aiming to become a global specialized player -Focusing on Research Division activities-

Drug Discovery Research for Sumitomo Dainippon Pharma Co., Ltd. aiming to become a global specialized player -Focusing on Research Division activities-

878. Antimicrobial Susceptibility of Pathogens Isolated from Surgical Site Infections in Japan: Comparison of Data from Nationwide Surveillance Studies Conducted in 2010, 2014–2015 and 2018-2019

BackgroundA nationwide survey was conducted in Japan from 2018–2019 to investigate the antimicrobial susceptibility of pathogens isolated from surgical site infections (SSI).MethodsThe resulting data were compared with that obtained in earlier surveys, conducted in 2010, 2014–2015, and 2018-2019.ResultsSeven main organisms were collected, and in total 2081 isolates were studied. Although a significant increase of extended-spectrum β-lactamase (ESBL) producing organisms among Enterobacteriaceae was demonstrated in 2014–15 (13.5%) compared with 2010 (5.3%), the incidence remained 6.6% in 2018–19. Only one carbapenemase-producing Enterobacteriaceae isolates were identified in the 2018–2019 study. The geometric mean (GM) MICs for ESBL producing isolates in 2018–2019 were 0.08 µg/mL for meropenem, 2.67 µg/mL for tazobactam/piperacillin, 0.40 µg/mL for tazobactam/ceftolozane, 6.35 µg/mL for cefoxitin, and 1.12 µg/mL for gentamycin. Antibiotic susceptible rate in Pseudomonas aeruginosa was 95.5% in meropenem, 93.9% in piperacillin/tazobactam, 100% in tazobactam/ceftolozane, 97.0% in cefepime, 90.9% in ciprofloxacin, and 86.4% in gentamycin. There was no significant difference in methicillin resistance rate of Staphylococcus aureus isolates among 3 study periods (72.0% in 2010, 53.4% in 2014–2015, and 63% in 2018-19). MRSA isolates with a vancomycin MIC of 2μg/mL accounted for 9.7% in 2010, 1.2% in 2014–2015, and 3.1% in 2018-19. GM MICs for MRSA isolates were 2.09 µg/mL for linezolid, 0.32 µg/mL for tedizolid, and 0.61 µg/mL for daptomycin. GM MICs in linezolid and daptomycin for the isolates in 2018–19 tended to be increased compared with isolates in 2010 (1.74 to 2.09 and 0.35 to 0.61 µg/mL, respectively). More than 90% of isolates belonging to the Bacteroides fragilis group remained susceptible to tazobactam/piperacillin, meropenem, and metronidazole. In contrast, lower levels of susceptibility were observed for moxifloxacin (65.3%), cefmetazole (47.2%) and clindamycin (38.9%). In cefoxitin, non-fragilis Bacteroides isolates had lower rates of antibiotic susceptibility compared with B. fragilis. (51.3% vs. 81.8%).ConclusionOverall, the surveillance data clarified trends in antimicrobial susceptibility for organisms commonly associated with SSI.DisclosuresYoshio Takesue, M.D, Ph.D, Astellas Pharma Inc (Speaker’s Bureau)MSD Japan (Speaker’s Bureau)Sumitomo Dainippon Pharma Co. Ltd. (Grant/Research Support) Hiroshige Mikamo, M.D, Ph.D, Astellas Pharma Inc. (Grant/Research Support, Speaker’s Bureau)MSD Japan (Grant/Research Support, Speaker’s Bureau)Pfizer Japan Inc. (Grant/Research Support)Sumitomo Dainippon Pharma Co., Ltd (Grant/Research Support, Speaker’s Bureau)

1205. Protectin D1 Induced by Clostridium butyricum MIYAIRI 588 Has an Anti-inflammatory Effects on Antibiotic-induced Intestinal Disorder

BackgroundThe administration of Clostridium butyricum MIYAIRI 588 (CBM 588) upregulates protectin D1,the anti-inflammatory lipid metabolites, in colon tissue under the antibiotic therapy. However, how CBM 588 induces protectin D1 nor whether the metabolite has anti-inflammatory effects on antibiotic-induced enteritis are unclear. Therefore, we evaluated the effect of CBM 588 on lipid metabolism and protectin D1 on immunological functions in colon tissue.MethodsMice were divided into five groups and clindamycin (CLDM), CBM 588 and/or protectin D1 were administered for 4 days (1. Control, 2. CLDM group, 3. CBM 588 group, 4. CLDM plus CBM 588 group and 5. CLDM plus protectin D1 group). After 4 days of administration, mice were reared for an additional 4 days. On day 8, colon tissues were removed to measure lipid metabolites with LC-MS/MS. Also, cytokines, lipid metabolism relative genes, enzymes were measured with qRT-PCR and ELISA.ResultsIn the CBM588 treatment group, protectin D1, α-linolenic acid, eicosapentaenoic acid (EPA) and autoxidation product of DHA (docosahexaenoic acid) were significantly increased, compared with CLDM group and control. At the same time, genes expression levels of polyunsaturated fatty acids (PUFAs) receptors, G-protein coupled receptor 120 (GPR120) and a DHA to protectin D1 metabolizing enzyme 15- lipoxygenase (LOX) in colon tissue increased. Il-4 produced by Th2 cells, also increased in CBM588 treated groups even under CLDM co-administration. In addition, similar to CBM 588, protectin D1 administration suppressed mice’s weight loss due to gut inflammation, decreased inflammatory cytokines, while anti-inflammatory cytokine IL-10 and TGF-β1 increased.PUFAs metabolism cascade induced by CBM 588. Lipid metabolism relative genes, pro/anti-inflammatory cytokines and body weight. ConclusionOur data suggested that CBM 588 stimulated PUFAs metabolism in the intestinal tract, and that PUFAs were signaled to Th2 cells as a ligand of GPR120. It was speculated that the stimulated Th2 cells produced IL4 and activated 15-LOX, resulting in the induction of protectin D1. Also, it became clear that protectin D1 induced anti-inflammatory cytokines in controlling antibiotic-induced gut inflammation. We provide as a new insight that lipid metabolism induction for the treatment of gut inflammatory diseases with CBM 588.Anti-inflammatory pathway of protectin D1 induced by CBM 588. Disclosures Hiroshige Mikamo, M.D, Ph.D, Astellas Pharma Inc. (Grant/Research Support, Speaker’s Bureau)MSD Japan (Grant/Research Support, Speaker’s Bureau)Pfizer Japan Inc. (Grant/Research Support)Sumitomo Dainippon Pharma Co., Ltd (Grant/Research Support, Speaker’s Bureau)

The rebirth of lithium as the archetypal mood stabilizer.

The serendipitous discovery of lithium's efficacy for the treatment of manic excitement dates back to initial observations by the Danish psychologist Carl Lange in 1886 who theorised that patients with manic-depressive illness had "cerebral gout" for which he suggested lithium salts because lithium could dissolve urate stones. Modern use was triggered by Cade in Melbourne in 1949, while its efficacy for the management of manic episodes and for the prophylaxis of both manic and bipolar depressive episodes was empirically confirmed by Mogens Schou in Denmark.

Phase 1 Study of Alvocidib (DSP-2033) in Combination with Cytarabine/Mitoxantrone (ACM) or Cytarabine/Daunorubicin (A+7+3) in Japanese Patients (Pts) with Acute Myeloid Leukemia (AML)

Phase 1 Study of Alvocidib (DSP-2033) in Combination with Cytarabine/Mitoxantrone (ACM) or Cytarabine/Daunorubicin (A+7+3) in Japanese Patients (Pts) with Acute Myeloid Leukemia (AML)