1: Impact of Amyloid and Tau PET on Changes in Diagnosis and Patient Management.
Science of the Month - November 2022
Neurology.
First published September 29, 2022, DOI: https://doi.org/10.1212
Sho Shimohama, Toshiki Tezuka, Keisuke Takahata , Shogyoku Bun, Hajime Tabuchi, Morinobu Seki, Yuki Momota, Natsumi Suzuki, Ayaka Morimoto, Yu Iwabuchi, Masahito Kubota, Yasuharu Yamamoto, Yasunori Sano, Ryo Shikimoto, Kei Funaki, Yu Mimura, Yoshinori Nishimoto, Ryo Ueda, Masahiro Jinzaki, Jin Nakahara, Masaru Mimura, Daisuke Ito
Alzheimer's disease, the leading cause of dementia, is said to account for over 60% of all dementia cases. Currently, dementia is diagnosed comprehensively through methods including neuropsychological tests, head MRI, and cerebral blood flow tests. However, none of these are definitive, and the misdiagnosis rate is reportedly 20–40%. This high rate of misdiagnosis is a major obstacle to clinical research, appropriate treatment, and the selection of nursing care. In this study, a team from our hospital's Memory Center and the National Institutes for Quantum Science and Technology found that using amyloid PET and tau PET scans in combination improves dementia diagnosis by approximately 35% and treatment and management by about 30%. Furthermore, many cognitively normal individuals also tested positive on PET scans, suggesting the tests are also useful for pre-symptomatic and risk diagnosis. The findings of this study are drawing attention as research that could significantly impact the approval process for Alzheimer's disease antibody drugs, which have been a recent focus.
(Daisuke Ito, Department of Physiology, Class of '71)
2: Identification of Quiescent LGR5+ Stem Cells in the Human Colon
Gastroenterology
Ishikawa K, Sugimoto S, Oda M, Fujii M, Takahashi S, Ohta Y, Takano A, Ishimaru K, Matano M, Yoshida K, Hanyu H, Toshimitsu K, Sawada K, Shimokawa M, Saito M, Kawasaki K, Ishii R, Taniguchi K, Imamura T, Kanai T, Sato T.
Humans are larger and have longer lifespans than mice, undergoing more cell divisions and accumulating more genetic mutations. Why, then, are humans less prone to cancer? It is because the human cell cycle is slower. While research on intestinal epithelial stem cells has historically been conducted in mice, the function of human colonic stem cells and their role in epithelial injury and regeneration had not been elucidated. In this study, we successfully visualized and observed the in vivo behavior of human colonic stem cells by three-dimensionally culturing normal colonic epithelium from patients using organoids, combined with genome editing technology and orthotopic colon transplantation. Many human colonic stem cells were found to exist in a quiescent state, expressing p27. We also demonstrated in an in vivo model that these quiescent stem cells, which normally proliferate slowly, are resistant to epithelial injury and accelerate their proliferation during regeneration, and that this quiescent state is regulated by TGF-β. This research is expected to become a cornerstone for understanding epithelial regeneration in various organs and the mechanisms of cancer development.
(Keiko Ishikawa, Department of Internal Medicine (Gastroenterology), Class of '91; Toshiro Sato, Department of Organoid Medicine, Class of '76)
3: Gene therapy using genome-edited iPS cells for targeting malignant glioma
Bioengineering and Translational Medicine.
2022 Sep 10; doi.org/10.1002/btm2.10406
Ryota Tamura, Hiroyuki Miyoshi, Kent Imaizumi, Masahiro Yo, Yoshitaka Kase, Tsukika Sato, Mizuto Sato, Yukina Morimoto, Oltea Sampetrean, Jun Kohyama, Munehisa Shinozaki, Atsushi Miyawaki, Kazunari Yoshida, Hideyuki Saya, Hideyuki Okano, Masahiro Toda
Malignant gliomas have a poor prognosis due to the presence of invasive and treatment-resistant glioma stem cells (GSCs). In this report, we developed a therapy targeting tumor invasiveness that uses human iPS cell-derived neural stem cells (NSCs) as a delivery vehicle. First, we identified EphB-ephrinB and CXCL12-CXCR4 signaling as the molecules responsible for the migratory ability of NSCs toward glioma cells. Next, we selected yCD-UPRT (which converts the prodrug 5-FC into the anticancer drug 5-FU) as the therapeutic gene to be introduced into iPS cells. However, because gene introduction via viral vectors resulted in random chromosomal insertion and gene inactivation, we used CRISPR/Cas9 to identify the optimal insertion site to achieve constitutive gene expression. The therapeutic NSCs established in this way demonstrated a high therapeutic effect against GSC models. We believe this research and development, which combines cell therapy and gene therapy, will serve as a platform applicable to various gene and cell therapies.
Our co-author, Dr. Hiroyuki Miyoshi, passed away suddenly during the course of this research. We express our deepest gratitude for his immense contributions to the advancement of this study.
(Ryota Tamura, Department of Neurosurgery, Class of '89; Masahiro Toda [corresponding author]; Hideyuki Okano, Department of Physiology)
Other Publications
1: The complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure.
Nat Commun.
nuary 5, 2021 118 (1) e2012482118; DOI: 10.1073
Shogo Ito, Hisayuki Hashimoto, Hiroyuki Yamakawa, Dai Kusumoto, Yohei Akiba, Takahiro Nakamura, Mizuki Momoi, Jin Komuro, Toshiomi Katsuki, Mai Kimura, Yoshikazu Kishino, Shin Kashimura, Akira Kunitomi, Mark Lachmann, Masaya Shimojima, Gakuto Yozu, Chikaaki Motoda, Tomohisa Seki, Tsunehisa Yamamoto, Yoshiki Shinya, Takahiro Hiraide, Masaharu Kataoka, Takashi Kawakami, Kunimichi Suzuki, …Shinsuke Yuasa
2: Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease
Am J Respir Crit Care Med.
2022 Jul 11. doi: 10.1164/rccm.202111-2606OC
Takafumi Kato, Takanori Asakura, Caitlin E Edwards, Hong Dang, Yu Mikami, Kenichi Okuda, Gang Chen, Ling Sun, Rodney C Gilmore, Padraig Hawkins, Gabriela De la Cruz, Michelle R Cooley, Alexis B Bailey, Stephen M Hewitt, Daniel S Chertow, Alain C Borczuk, Steven Salvatore, Fernando J Martinez, Leigh B Thorne, Frederic B Askin, Camille Ehre, Scott H Randell, Wanda K O'Neal, Ralph S Baric, Richard C Boucher, NIH COVID-9 Autopsy Consortium
3: Multinational Federated Learning Approach to Train ECG and Echocardiogram Models for Hypertrophic Cardiomyopathy Detection.
Circulation.
2022;146(10):755-769. [Article]
Goto S, Solanki D, John JE, Yagi R, Homilius M, Ichihara G, Katsumata Y, Gaggin HK, Itabashi Y, MacRae CA, Deo RC.