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52. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

Author

Miller, Timothy M, Cudkowicz, Merit E, Andrews, Jinsy A, Hesters, Adele, Kermorvant, Hugo, Lacomblez, Lucette, Forestier, Nadine Le, Lenglet, Thimotée, Retail, Maryvonne, Ruiz Del Mar Amador, Maria, Salachas, François, Shotar, Eimad, Sourour, Nader, Babu, Suma, Dorst, Johannes, Froehlich, Elke, Fromm, Andrea, Kandler, Katharina, Langer, Eva, Leichtle, Sarah, Ludolph, Albert, Mayer, Kristina, Michels, Sebastian, Raubold, Sabine, Benatar, Michael, Schuster, Joachim, Weiland, Ulrike, Wiesenfarth, Maximilian, Witzel, Simon, Calvo, Andrea, Canosa, Antonio, Casale, Federico, Chiò, Adriano, Fuda, Giuseppe, Grassano, Maurizio, McDermott, Christopher J, Marchese, Giulia, Moglia, Cristina, Palumbo, Francesca, Salamone, Paolina, Ajiki, Takahiro, Akasaka, Aya, Ando, Masahiro, Arata, Hitoshi, Asuka, Kitamura, Baba, Kosuke, Cochrane, Thos, Bekku, Goichi, Chiba, Tomoya, Date, Yugaku, Eriko, Takeuchi, Hashiguchi, Akihiro, Hatatori, Ritsuko, Hayano, Eri, Hayashi, Yuto, Higashi, Keiko, Higuchi, Eriko, Chary, Sowmya, Hiramatsu, Yu, Horikawa, Rui, Ikenaka, Kensuke, Ishiura, Hiroyuki, Ito, Daisuke, Kawai, Sachiko, Kikuchi, Junko, Kuzuyama, Haruko, Li, Xuehong, Matsumoto, Chika, Chew, Sheena, Matsuura, Eiji, Michizono, Kumiko, Mitsui, Jun, Mitsutake, Akihiko, Mochizuki, Hideki, Nagamatsu, Akemi, Nagano, Seiichi, Nakamura, Tomonori, Naruse, Hiroya, Ogasawara, Asuka, Zhu, Han, Okada, Kensuke, Okamoto, Yuji, Okuno, Tatsusada, Oyama, Satoshi, Ozono, Tatsuhiko, Sakiyama, Yusuke, Sakuishi, Kaori, Seki, Morinobu, Shibata, Shota, Shimizu, Mikito, Wu, Fan, Takahata, Katsunori, Takahito, Yoshizaki, Takashima, Hiroshi, Takeichi, Hiroko, Tashiro, Yuichi, Toda, Tatsushi, Tomizu, Yuki, Tomoya, Wadayama, Ujiakira, Nishiike, Yashita, Daiki, Nestorov, Ivan, Al-Chalabi, Ammar, Alix, James, Bangalore, Priyadarshini, Blackburn, Daniel, Chiwera, Theresa, Clegg, Rosie, Collins, Alexis, Cooper-Knock, Jonathan, Emery, Anna, Franklin, John, Genge, Angela, Graham, Danielle, Green, Louisa, Harvey, Callum, Hobson, Esther, Islam, Mahjabim, Jenkins, Thomas Michael, Kazoka, Mbombe, Kelly, Gillian, Korley, Mercy, Madarshahaian, Daniel, Mayl, Keith, Sun, Peng, McDermott, Christopher John, Radford, Alex, Shaw, Christopher, Shaw, Pamela J, Sidebottom, Joe, Smart, Lynne, Sreedharan, Jemeen, Stone, Ben, Tsironis, Theocharis, Tuddenham, Lee, McNeill, Manjit, Verber, Nick, Wollff, Helen, Young, Stacy, Zis, Panagiotis, Adamo, Ashley, Ahmed, Arubah, Ajroud-Driss, Senda, Alameda, Gustave, Arcila-Londono, Ximena, Fanning, Laura, Baird, Candy, Bazan, Tracy, Berry, James, Bordeau, Jane, Bradford, Wendy, Brook, Nyda, Brown, Lauren, Bucelli, Robert C, Ferguson, Toby A, Buckner, Katherine, Budler, Michael W, Burba, Lindita, Burke, Katherine, Calhoun, Ashley D, Campbell, Sarah, Carey, Judith, Caristo, Irys B, Carty, Simon, Chan, Emmanuel, Fradette, Stephanie, Chaudhry, Vinay, Chen, Ricky, Chow, Saephanh, Clawson, Lora L, Clemens, Mitchell, Cloninger, Suzann E, Coleman-Wood, Krista, Cooper, Thomas N, Cummings, Arlena, Daniels, Jacquelyn, VALOR, DeSaro, Pamela, DeWitt, Michelle, Dedi, Brixhilda, Dempsey, Debbie, Denny, Carol, Doherty, Jenna, Doherty, Leana, Donahue, Megan, Doyle, Michael, Duncan, Jessie, Group, OLE Working, Elman, Lauren, Eloge, Christine M, Echiti, Desirae R, Ferrey, Dominic, Fournier, Christina, Fukumura, Yuriko, Gallagher, Katherine, Garaycoa, Jessica, Garrett, Mark, Gibson, Richard L, Beullens, Lien, Gifford, Ryan, Glass, Jonathan D, Gogol, Danuta, Golden, Shea, Gonzalez, Alexa, Goodman, Ira, Goolsby, Christopher, Goslin, Kimberly, Goulbourne, Michael, Granit, Volkan, Claeys, Kristl, Grignon, Anne-Laure, GuhaRay, Adreeja, Guide, Debra, Gundogdu, Melek Betul, Gutierrez, Gil, Hastings, Debbie, Hayzen, Colleen, Herzog, Hilary, Holloway, Raegan, Jacobs, Gabriel, Claeys, Thomas, Jacobsen, Bill, James, Virginia, Jenkins, Liberty, Jockel-Balsarotti, Jennifer, Johnson, Linda Carol, Jose, Sunil, Joslin, Benjamin, Karanja, Elizabeth, Katz, Jonathan, Keener, Anthony, Couwelier, Goedele, Kittle, Gale, Klein, Sara, Kreple, Collin, Rebecca, Rebecca, Kuenzler, Kuenzler, Kusnir, Jorge, Labbe, Kristen, Lachica-Encinas, Nicolet, Ladha, Shafeeq, Leimer, Lesli, D'Hondt, Ann, Levy, Michael, Levy, Wendy, Li, Yingji, Likanje, Marie-France, Livigni, Rebecca, Locatelli, Eduardo, Luppino, Sarah, Malcolm, Amber, Maragakis, Nicholas, Marin, Horia, Debien, Elisa, Markowitz, Clyde, Markway, Jesse, McCaffrey, Alexandra, McCoy, Arita, McCoy Gross, Kelly, Mehta, Kush, Meyer, Robert, Milan, Jennifer, Miller, Timothy, Miller, Robert G, de Keersmaecker, Sebastiaan, Morales, Francisco, Mosmiller, Elizabeth, Mott, Donovan, Moulton, Kelsey, Murphy, Christine A, Negron, Tirso, Nelson, Cassandra, Newman, Daniel S, Nissinen, Janne Kristoffer, Norman, Andrew, Della Faille, Laetitia, Ohkubo, Takuya, Olney, Nicholas, Ortiz, Natasha, Oskarsson, Bjorn, Pace, Mitchell, Packard, Kathleen, Padgett, Denny, Paganoni, Sabrina, Paredes, Maria E, Parker, Elizabeth, Delmotte, Koen, Partlow, Ann, Pattee, Gary L, Paulett, Jany, Pelot, Antoinette, Pfeifer, Kyle M, Pijanowski, Olivia, Pioro, Erik, Polak, Meraida, Prakash, Ahalya, Previte, Rosemarie, Depoortere, Sofie, Pukenas, Bryan, Quinn, Colin, Ravits, John, Razavi, Ryan, Regan, Tyler, Riley, Kristen M, Roth, Heather, Sanders, Danica, Scalia, Jennifer, Schmidt, Emma, de Velder, Laura, Schwen, Edward, Shah, Jaimin, Shah, Stuti, Shefner, Jeremy, Sheldon, Danielle, Simmons, Karon, Singh, Navneet K, Singleton, Jessica, Smiley, Richard, Smith, William B, Dobbels, Laurens, Smith, Sean, Sotirchos, Elias, Sorenson, Eric, Staff, Nathan, Steele, Julie, Steijlen, Kara, Stirrat, Taylor, Stoica, George S, Strong, Stephanie, Sufit, Robert, Sobue, Gen, Gijs, Jeroen, Sultze, Jane, Swartz, Amy, Szymanski, April, Tay, Anna, Thakore, Nimish, Thiessen, Diana, Thotala, Sukrutha, Trudell, Randall G, Turcotte, Nicole, Turner, Michelle, Horckmans, Simon, Uchil, Alpa, Upadhyay, Vihar, Usman, Uzma, Vallis, Anne, Vaporean-Bussey, Danielle, Vladimirova, Valentine, Weber, Harli, Winbigler, Jennifer, Wojanowski, Heather, Wulf, Charlie, Lamaire, Nikita, Yasek, Julia, Yoo, Stephanie, Zivalic, Hannah, Cole, Alexandra, File, Greta, Foate, Jeremy, Mason, Deborah, Newton, Susan, Roberts, Stephen, Sellwood, Cory Dean, Liessens, Hannelore, Swan, James, Werno, Anja, Zhong, Cathy, Masrori, Pegah, Nysten, Celine, Schotte, Caroline, Serrien, Anouk, Swinnen, Bart, Tilkin, Petra, van Daele, Sien, Van Damme, Philip, Vynckier, Jan, Wouters, Anke, Abrahao, Agessandro, Angle, Mark, Badawy, Mohamed, Berube, Maxime, Bertone, Vanessa, Cooper, Sarah Marie, Dobrowolski, Peter, Fong, Helen, Hannouche, Matthew, Hartley, Denise, Hogan, Michael, Johnston, Wendy, Khalfallah, Yousra, Korngut, Lawrence, Kroetsch, Gina, Letourneau, Justin, Magnussen, Claire, Martinez, Jose, Massie, Rami, Mobach, Theodore, Mookshah, Jahan, Ozelsel, Timur, Parks, Andrea, Petrillo, Janet, Pfeffer, Gerald, Ludolph, Albert C, Pham, Shirley, Phung, Liane, Shiungsun, Rodney, Pi-Shan, Li, Santos, Denizart, Salmon, Kristiana, Saunders, Natalie, Sembinelli, Dylan, Tymkow, Kelsey, Wong, Berchman, Zinman, Lorne, Karlsborg, Merete, Pedersen Lomholt, Therese, Nilsson, Sigrid, Salvesen, Lisette, Skov, Pernille, Svenstrup, Kristen, Bruneteau, Gaelle, Calerencon, Frederic, and Guimaraes Costa, Raquel

Subjects
Adult, drug effects [Recovery of Function], Spinal, Oligonucleotides, blood [Neurofilament Proteins], administration & dosage [Oligonucleotides, Antisense], tofersen, Injections, blood [Amyotrophic Lateral Sclerosis], pharmacology [Oligonucleotides, Antisense], Superoxide Dismutase-1, Double-Blind Method, Neurofilament Proteins, Humans, ddc:610, Antisense, Injections, Spinal, Biomarkers, Recovery of Function, Amyotrophic Lateral Sclerosis, Oligonucleotides, Antisense, blood [Biomarkers], drug therapy [Amyotrophic Lateral Sclerosis], therapeutic use [Oligonucleotides, Antisense], SOD1 protein, human, General Medicine, genetics [Superoxide Dismutase-1], genetics [Amyotrophic Lateral Sclerosis], cerebrospinal fluid [Biomarkers], cerebrospinal fluid [Superoxide Dismutase-1], cerebrospinal fluid [Amyotrophic Lateral Sclerosis]
Abstract

The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS).In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort).A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients.In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

Published
2022
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54. Pharmacokinetics/pharmacodynamics analysis and establishment of optimal dosing regimens using unbound cefmetazole concentration for patients infected with Extended‐Spectrum β‐lactamase producing Enterobacterales (ESBL‐E).

Author

Namiki, Takaya, Yokoyama, Yuta, Hashi, Hideki, Oda, Rentaro, Jibiki, Aya, Kawazoe, Hitoshi, Matsumoto, Kazuaki, Suzuki, Sayo, and Nakamura, Tomonori

Subjects
HIGH performance liquid chromatography, MONTE Carlo method, ELECTRONIC health records, PHARMACOKINETICS, SOLID phase extraction
Abstract

Study Objective: Establish methods for measuring cefmetazole (CMZ) concentrations conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis using unbound CMZ concentrations for extended‐spectrum β‐lactamase producing enterobacterales (ESBL‐E) and investigate optimal dosing regimens for not undergoing hemodialysis (non‐HD) and undergoing hemodialysis (HD) patients. Design: Prospective observational study. Patients: Included patients treated with CMZ who provided written informed consent and were admitted to the Tokyo Bay Urayasu Ichikawa Medical Center between August 2021 and July 2022. Measurements: Total and Unbound CMZ concentration was measured by high‐performance liquid chromatography (HPLC) with solid‐phase extraction and ultrafiltration. Setting: Determining the CMZ dosing regimen involved modified creatinine clearance (CLCR) with measured body weight (BW) using the Cockcroft–Gault equation. For non‐HD patients, blood samples were collected during at least three points. For patients undergoing HD, 1 g was administered via intravenous infusion, or rapid intravenous injection after HD, or 30 min before the end of HD. Blood samples were collected before HD (pre‐HD), and 1 and 3 h after starting HD and post‐HD. All blood samples were collected at steady‐state. Patient information was collected from electronic medical records. An unbound PK model was constructed for the non‐HD patients. A nomogram was constructed using Monte Carlo simulations with a 90% probability of target attainment at 70% free time above the minimum inhibitory concentration (MIC). For the HD patients, a nomogram was used to determine the optimal dosing regimen for each HD schedule. Main Results: CMZ measurement methods were established. A model analysis of unbound PK in 37 non‐HD patients incorporated creatinine clearance (CLCR) using the Cockcroft–Gault equation, albumin (ALB) for clearance and body weight (BW) for the volume of distribution. In Monte Carlo simulations, nomograms corresponding to the MIC (known and unknown) were generated for each covariate. Using the nomogram, non‐HD patients with an ESBL‐E MIC of 8 mg/L, a BW of 60 kg, an ALB of 25 g/L, and a CLCR of 60 mL/min required administration of 2 g every 6 h (1‐ and 3‐h infusions). Unbound PK model parameters were calculated for 7 HD patients, and the optimal dosing regimens following PK/PD were determined for each HD schedule. In HD patients, the regimen after and during HD was established using a treatment that was effective up to an ESBL‐E MIC of 4 mg/L. Conclusions: The nomogram for CMZ regimens established by PK/PD analysis of measured CMZ concentrations enables optimal CMZ dosing for ESBL‐E‐infected patients. [ABSTRACT FROM AUTHOR]

Published
2024
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58. Robust In Vitro Induction of Human Germ Cell Fate from Pluripotent Stem Cells

Author

Sasaki, Kotaro, Yokobayashi, Shihori, Nakamura, Tomonori, Okamoto, Ikuhiro, Yabuta, Yukihiro, Kurimoto, Kazuki, Ohta, Hiroshi, Moritoki, Yoshinobu, Iwatani, Chizuru, Tsuchiya, Hideaki, Nakamura, Shinichiro, Sekiguchi, Kiyotoshi, Sakuma, Tetsushi, Yamamoto, Takashi, Mori, Takahide, Woltjen, Knut, Nakagawa, Masato, Yamamoto, Takuya, Takahashi, Kazutoshi, Yamanaka, Shinya, and Saitou, Mitinori

Published
2015
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66. Clinical phenotypic diversity ofNOTCH2NLC-related disease in the largest case series of inherited peripheral neuropathy in Japan

Author

Ando, Masahiro, primary, Higuchi, Yujiro, additional, Yuan, Jun-Hui, additional, Yoshimura, Akiko, additional, Dozono, Mika, additional, Hobara, Takahiro, additional, Kojima, Fumikazu, additional, Noguchi, Yutaka, additional, Takeuchi, Mika, additional, Takei, Jun, additional, Hiramatsu, Yu, additional, Nozuma, Satoshi, additional, Nakamura, Tomonori, additional, Sakiyama, Yusuke, additional, Hashiguchi, Akihiro, additional, Matsuura, Eiji, additional, Okamoto, Yuji, additional, Sone, Jun, additional, and Takashima, Hiroshi, additional

Published
2023
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70. Prognostic Model of Baseline Medications plus Neutrophil-to-lymphocyte Ratio in Patients with Advanced Non-small-cell Lung Cancer Receiving Immune Checkpoint Inhibitor plus Platinum Doublet: A Multicenter Retrospective Study

Author

Nasu, Izumi, primary, Kondo, Masahiro, additional, Uozumi, Ryuji, additional, Takada, Shinya, additional, Nawata, Shuichi, additional, Iihara, Hirotoshi, additional, Okumura, Yohei, additional, Takemoto, Masashi, additional, Mino, Kozo, additional, Sasaki, Tadanori, additional, Hirose, Chiemi, additional, Aomori, Tohru, additional, Shimano, Rena, additional, Maeno, Ken, additional, Oizumi, Satoshi, additional, Kusumoto, Sojiro, additional, Ohno, Yasushi, additional, Ikemura, Shinnosuke, additional, Takai, Daiya, additional, Hara, Azusa, additional, Kawazoe, Hitoshi, additional, and Nakamura, Tomonori, additional

Published
2023
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77. Patient-associated risk factors for severe anemia in patients with advanced ovarian or breast cancer receiving olaparib monotherapy: A multicenter retrospective study

Author

Tashiro, Ryota, primary, Kawazoe, Hitoshi, additional, Mamishin, Kanako, additional, Seto, Keisuke, additional, Udagawa, Ryoko, additional, Saito, Yoshimasa, additional, Hashimoto, Hironobu, additional, Shimoi, Tatsunori, additional, Yonemori, Kan, additional, Yonemura, Masahito, additional, Terakado, Hiroyuki, additional, Kawasaki, Toshikatsu, additional, Furukawa, Tetsuya, additional, and Nakamura, Tomonori, additional

Published
2022
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85. Usefulness of Practitioner-Led Pancreatic Cancer Screening

Author

Matsumoto, Kazuya, primary, Kushiyama, Yoshinori, additional, Izumi, Akio, additional, Ohnishi, Koji, additional, Miura, Masahiko, additional, Ohuchi, Yasufumi, additional, Hori, Ikuko, additional, Nakamura, Tomonori, additional, Hori, Kotaro, additional, Koshino, Kenji, additional, Kobayashi, Junko, additional, Yoshino, Nagisa, additional, Hoshino, Ushio, additional, Okumura, Takekiyo, additional, Tanimura, Takashi, additional, Tanaka, Shinsuke, additional, Tanaka, Shino, additional, Nabika, Tadashi, additional, Nozu, Tatsuaki, additional, Wakatsuki, Yutaka, additional, Katayama, Syunsuke, additional, Yoshioka, Shizue, additional, Ito, Kenichi, additional, Uchida, Akiko, additional, Yuhara, Noriji, additional, Noma, Hisashi, additional, and Isomoto, Hajime, additional

Published
2022
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86. Design, Synthesis, and Monoamine Oxidase B Selective Inhibitory Activity of N-Arylated Heliamine Analogues

Author

Yamada, Makito, primary, Hirose, Yu, additional, Lin, Bangzhong, additional, Fumimoto, Megumi, additional, Nunomura, Kazuto, additional, Natchanun, Sirimangkalakitti, additional, Takahashi, Naoyuki, additional, Ohki, Yuuta, additional, Sako, Makoto, additional, Murai, Kenichi, additional, Harada, Kazuo, additional, Arai, Masayoshi, additional, Suzuki, Sayo, additional, Nakamura, Tomonori, additional, Haruta, Junichi, additional, and Arisawa, Mitsuhiro, additional

Published
2022
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87. Multi-type RFC1 repeat expansions as the most common cause of hereditary sensory and autonomic neuropathy

Author

Yuan, Jun-Hui, primary, Higuchi, Yujiro, additional, Ando, Masahiro, additional, Matsuura, Eiji, additional, Hashiguchi, Akihiro, additional, Yoshimura, Akiko, additional, Nakamura, Tomonori, additional, Sakiyama, Yusuke, additional, Mitsui, Jun, additional, Ishiura, Hiroyuki, additional, Tsuji, Shoji, additional, and Takashima, Hiroshi, additional

Published
2022
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89. Simultaneous quantification of dasatinib, nilotinib, bosutinib, and ponatinib using high‐performance liquid chromatography–Photodiode array detection

Author

Yokoyama, Yuta, primary, Nozawa, Eiji, additional, Morita, Miho, additional, Ishikawa, Emi, additional, Mori, Takehiko, additional, Sakurai, Masatoshi, additional, Kikuchi, Taku, additional, Matsuki, Eri, additional, Yamazaki, Rie, additional, Kataoka, Keisuke, additional, Jibiki, Aya, additional, Kawazoe, Hitoshi, additional, Suzuki, Sayo, additional, and Nakamura, Tomonori, additional

Published
2022
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90. 3EZ, 20Ac-ingenol-induced Apoptosis in Chemoresistant Cancers With Cyclin D1 Accumulation

Author

Shohei Miyata, Susumu Kitanaka, and Nakamura Tomonori

Subjects
Cyclin-Dependent Kinase Inhibitor p21, Cancer Research, DNA damage, Apoptosis, Caspase 3, Ataxia Telangiectasia Mutated Proteins, Cyclin A, Irinotecan, Histones, Cyclin D1, Cell Line, Tumor, Humans, Phosphorylation, Protein kinase B, Cell Proliferation, Glycogen Synthase Kinase 3 beta, Cell growth, Chemistry, PTEN Phosphohydrolase, General Medicine, Enzyme Activation, Oncology, Drug Resistance, Neoplasm, Cancer cell, Cancer research, DNA fragmentation, Diterpenes, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

Background/aim The topoisomerase 1 catalytic inhibitor 3EZ, 20Ac-ingenol specifically induces apoptosis through the activation of ATR and the up-regulation of PTEN by enhancing the DNA damage response (DDR) in human B lymphoma (BALL-1) cells. The accumulation of cyclin D1 in cancer is known to be related to chemoresistance to DNA damage agents and nuclei of BALL-1 cells exhibit high levels of cyclin D1. However, 3EZ, 20Ac-ingenol effectively induced apoptosis of BALL-1 cells. Materials and methods Cell growth, protein levels, and apoptosis were determined by an MTT assay, immunoblotting and DNA fragmentation assay, respectively. Results 3EZ, 20Ac-ingenol strongly induced inhibition of cell proliferation and apoptosis in Jeko-1 and Panc-1 cell lines through the activation of tumor suppressor proteins and caspase 3. Conclusion 3EZ, 20Ac-ingenol-induced apoptosis might occur in cells with cyclin D1 accumulation through enhancing DDR, regardless of the cancer cell type.

Published
2020
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93. Ex vivo reconstitution of fetal oocyte development in humans and cynomolgus monkeys

Author

40909503, 90648429, 30535836, 50391892, Mizuta, Ken, Katou, Yoshitaka, Nakakita, Baku, Kishine, Aoi, Nosaka, Yoshiaki, Saito, Saki, Iwatani, Chizuru, Tsuchiya, Hideaki, Kawamoto, Ikuo, Nakaya, Masataka, Tsukiyama, Tomoyuki, Nagano, Masahiro, Kojima, Yoji, Nakamura, Tomonori, Yabuta, Yukihiro, Horie, Akihito, Mandai, Masaki, Ohta, Hiroshi, Saitou, Mitinori, 40909503, 90648429, 30535836, 50391892, Mizuta, Ken, Katou, Yoshitaka, Nakakita, Baku, Kishine, Aoi, Nosaka, Yoshiaki, Saito, Saki, Iwatani, Chizuru, Tsuchiya, Hideaki, Kawamoto, Ikuo, Nakaya, Masataka, Tsukiyama, Tomoyuki, Nagano, Masahiro, Kojima, Yoji, Nakamura, Tomonori, Yabuta, Yukihiro, Horie, Akihito, Mandai, Masaki, Ohta, Hiroshi, and Saitou, Mitinori

Abstract

In vitro oogenesis is key to elucidating the mechanism of human female germ-cell development and its anomalies. Accordingly, pluripotent stem cells have been induced into primordial germ cell-like cells and into oogonia with epigenetic reprogramming, yet further reconstitutions remain a challenge. Here, we demonstrate ex vivo reconstitution of fetal oocyte development in both humans and cynomolgus monkeys (Macaca fascicularis). With an optimized culture of fetal ovary reaggregates over three months, human and monkey oogonia enter and complete the first meiotic prophase to differentiate into diplotene oocytes that form primordial follicles, the source for oogenesis in adults. The cytological and transcriptomic progressions of fetal oocyte development in vitro closely recapitulate those in vivo. A comparison of single-cell transcriptomes among humans, monkeys, and mice unravels primate-specific and conserved programs driving fetal oocyte development, the former including a distinct transcriptomic transformation upon oogonia-to-oocyte transition and the latter including two active X chromosomes with little X-chromosome upregulation. Our study provides a critical step forward for realizing human in vitro oogenesis and uncovers salient characteristics of fetal oocyte development in primates.

Published
2022

94. Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity

Author

90648429, 50511812, 20432578, 20212805, Tsujihana, Kojiro, Tanegashima, Kosuke, Santo, Yasuko, Yamada, Hiroyuki, Akazawa, Sota, Nakao, Ryuta, Tominaga, Keiko, Saito, Risa, Nishito, Yasumasa, Hata, Ryu-Ichiro, Nakamura, Tomonori, Murai, Iori, Kono, Yuka, Sugawa, Maho, Tanioka, Miki, Egawa, Gyohei, Doi, Masao, Isa, Tadashi, Kabashima, Kenji, Hara, Takahiko, Okamura, Hitoshi, 90648429, 50511812, 20432578, 20212805, Tsujihana, Kojiro, Tanegashima, Kosuke, Santo, Yasuko, Yamada, Hiroyuki, Akazawa, Sota, Nakao, Ryuta, Tominaga, Keiko, Saito, Risa, Nishito, Yasumasa, Hata, Ryu-Ichiro, Nakamura, Tomonori, Murai, Iori, Kono, Yuka, Sugawa, Maho, Tanioka, Miki, Egawa, Gyohei, Doi, Masao, Isa, Tadashi, Kabashima, Kenji, Hara, Takahiko, and Okamura, Hitoshi

Abstract

The epidermis is the outermost layer of the skin and the body’s primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.

Published
2022

95. Resolution of the curse of dimensionality in single-cell RNA sequencing data analysis

Author

60793982, 60546993, 10432709, Imoto, Yusuke, Nakamura, Tomonori, Escolar, G, Emerson, Yoshiwaki, Michio, Kojima, Yoji, Yabuta, Yukihiro, Katou, Yoshitaka, Yamamoto, Takuya, Hiraoka, Yasuaki, Saitou, Mitinori, 60793982, 60546993, 10432709, Imoto, Yusuke, Nakamura, Tomonori, Escolar, G, Emerson, Yoshiwaki, Michio, Kojima, Yoji, Yabuta, Yukihiro, Katou, Yoshitaka, Yamamoto, Takuya, Hiraoka, Yasuaki, and Saitou, Mitinori

Abstract

Single-cell RNA sequencing (scRNA-seq) can determine gene expression in numerous individual cells simultaneously, promoting progress in the biomedical sciences. However, scRNA-seq data are high-dimensional with substantial technical noise, including dropouts. During analysis of scRNA-seq data, such noise engenders a statistical problem known as the curse of dimensionality (COD). Based on high-dimensional statistics, we herein formulate a noise reduction method, RECODE (resolution of the curse of dimensionality), for high-dimensional data with random sampling noise. We show that RECODE consistently resolves COD in relevant scRNA-seq data with unique molecular identifiers. RECODE does not involve dimension reduction and recovers expression values for all genes, including lowly expressed genes, realizing precise delineation of cell fate transitions and identification of rare cells with all gene information. Compared with representative imputation methods, RECODE employs different principles and exhibits superior overall performance in cell-clustering, expression value recovery, and single-cell–level analysis. The RECODE algorithm is parameter-free, data-driven, deterministic, and high-speed, and its applicability can be predicted based on the variance normalization performance. We propose RECODE as a powerful strategy for preprocessing noisy high-dimensional data.

Published
2022

96. Usefulness of Peptide Nucleic Acid (PNA)-Clamp Smart Amplification Process Version 2 (SmartAmp2) for Clinical Diagnosis of KRAS Codon12 Mutations in Lung Adenocarcinoma : Comparison of PNA-Clamp SmartAmp2 and PCR-Related Methods

Author

Araki, Takuya, Shimizu, Kimihiro, Nakamura, Katsunori, Nakamura, Tomonori, Mitani, Yasumasa, Obayashi, Kyoko, Fujita, Yukiyoshi, Kakegawa, Seiichi, Miyamae, Yohei, Kaira, Kyoichi, Ishidao, Takefumi, Lezhava, Alexander, Hayashizaki, Yoshihide, Takeyoshi, Izumi, and Yamamoto, Koujirou

Published
2010
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