Optimization of the proliferation and persistency of CAR T cells derived from human induced pluripotent stem cells

CARシグナルを補完する遺伝子改変により *iCAR-T細胞の固形がん治療効果が改善される. 京都大学プレスリリース. 2022-12-13.Genetic modifications boosting CAR signaling improve the therapeutic efficacy of iPSC-derived CAR-T cells against solid tumors. 京都大学プレスリリース. 2022-12-13.The effectiveness of chimaeric antigen receptor (CAR) T-cell immunotherapies against solid tumours relies on the accumulation, proliferation and persistency of T cells at the tumour site. Here we show that the proliferation of CD8αβ cytotoxic CAR T cells in solid tumours can be enhanced by deriving and expanding them from a single human induced-pluripotent-stem-cell clone bearing a CAR selected for efficient differentiation. We also show that the proliferation and persistency of the effector cells in the tumours can be further enhanced by genetically knocking out diacylglycerol kinase, which inhibits antigen-receptor signalling, and by transducing the cells with genes encoding for membrane-bound interleukin-15 (IL-15) and its receptor subunit IL-15Rα. In multiple tumour-bearing animal models, the engineered hiPSC-derived CAR T cells led to therapeutic outcomes similar to those of primary CD8 T cells bearing the same CAR. The optimization of effector CAR T cells derived from pluripotent stem cells may aid the development of long-lasting antigen-specific T-cell immunotherapies for the treatment of solid tumours

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020)

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.other authors: Yasuhiro Norisue, Satoru Hashimoto, Daisuke Hasegawa, Junji Hatakeyama, Naoki Hara, Naoki Higashibeppu, Nana Furushima, Hirotaka Furusono, Yujiro Matsuishi, Tasuku Matsuyama, Yusuke Minematsu, Ryoichi Miyashita, Yuji Miyatake, Megumi Moriyasu, Toru Yamada, Hiroyuki Yamada, Ryo Yamamoto, Takeshi Yoshida, Yuhei Yoshida, Jumpei Yoshimura, Ryuichi Yotsumoto, Hiroshi Yonekura, Takeshi Wada, Eizo Watanabe, Makoto Aoki, Hideki Asai, Takakuni Abe, Yutaka Igarashi, Naoya Iguchi, Masami Ishikawa, Go Ishimaru, Shutaro Isokawa, Ryuta Itakura, Hisashi Imahase, Haruki Imura, Takashi Irinoda, Kenji Uehara, Noritaka Ushio, Takeshi Umegaki, Yuko Egawa, Yuki Enomoto, Kohei Ota, Yoshifumi Ohchi, Takanori Ohno, Hiroyuki Ohbe, Kazuyuki Oka, Nobunaga Okada, Yohei Okada, Hiromu Okano, Jun Okamoto, Hiroshi Okuda, Takayuki Ogura, Yu Onodera, Yuhta Oyama, Motoshi Kainuma, Eisuke Kako, Masahiro Kashiura, Hiromi Kato, Akihiro Kanaya, Tadashi Kaneko, Keita Kanehata, Ken-ichi Kano, Hiroyuki Kawano, Kazuya Kikutani, Hitoshi Kikuchi, Takahiro Kido, Sho Kimura, Hiroyuki Koami, Daisuke Kobashi, Iwao Saiki, Masahito Sakai, Ayaka Sakamoto, Tetsuya Sato, Yasuhiro Shiga, Manabu Shimoto, Shinya Shimoyama, Tomohisa Shoko, Yoh Sugawara, Atsunori Sugita, Satoshi Suzuki, Yuji Suzuki, Tomohiro Suhara, Kenji Sonota, Shuhei Takauji, Kohei Takashima, Sho Takahashi, Yoko Takahashi, Jun Takeshita, Yuuki Tanaka, Akihito Tampo, Taichiro Tsunoyama, Kenichi Tetsuhara, Kentaro Tokunaga, Yoshihiro Tomioka, Kentaro Tomita, Naoki Tominaga, Mitsunobu Toyosaki, Yukitoshi Toyoda, Hiromichi Naito, Isao Nagata, Tadashi Nagato, Yoshimi Nakamura, Yuki Nakamori, Isao Nahara, Hiromu Naraba, Chihiro Narita, Norihiro Nishioka, Tomoya Nishimura, Kei Nishiyama, Tomohisa Nomura, Taiki Haga, Yoshihiro Hagiwara, Katsuhiko Hashimoto, Takeshi Hatachi, Toshiaki Hamasaki, Takuya Hayashi, Minoru Hayashi, Atsuki Hayamizu, Go Haraguchi, Yohei Hirano, Ryo Fujii, Motoki Fujita, Naoyuki Fujimura, Hiraku Funakoshi, Masahito Horiguchi, Jun Maki, Naohisa Masunaga, Yosuke Matsumura, Takuya Mayumi, Keisuke Minami, Yuya Miyazaki, Kazuyuki Miyamoto, Teppei Murata, Machi Yanai, Takao Yano, Kohei Yamada, Naoki Yamada, Tomonori Yamamoto, Shodai Yoshihiro, Hiroshi Tanaka & Osamu Nishid

Nanoscopic changes in the lattice structure of striated muscle sarcomeres involved in the mechanism of spontaneous oscillatory contraction (SPOC)

Muscles perform a wide range of motile functions in animals. Among various types are skeletal and cardiac muscles, which exhibit a steady auto-oscillation of force and length when they are activated at an intermediate level of contraction. This phenomenon, termed spontaneous oscillatory contraction or SPOC, occurs devoid of cell membranes and at fixed concentrations of chemical substances, and is thus the property of the contractile system per se. We have previously developed a theoretical model of SPOC and proposed that the oscillation emerges from a dynamic force balance along both the longitudinal and lateral axes of sarcomeres, the contractile units of the striated muscle. Here, we experimentally tested this hypothesis by developing an imaging-based analysis that facilitates detection of the structural changes of single sarcomeres at unprecedented spatial resolution. We found that the sarcomere width oscillates anti-phase with the sarcomere length in SPOC. We also found that the oscillatory dynamics can be altered by osmotic compression of the myofilament lattice structure of sarcomeres, but they are unchanged by a proteolytic digestion of titin/connectin – the spring-like protein that provides passive elasticity to sarcomeres. Our data thus reveal the three-dimensional mechanical dynamics of oscillating sarcomeres and suggest a structural requirement of steady auto-oscillation