Mechanistic insights into the selective stabilization of mammalian microRNAs

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 鈴木 勉, 東京大学教授 後藤 由季子, 東京大学教授 富田 耕造, 東京大学教授 泊 幸秀, 東京大学准教授 河原 正浩University of Tokyo(東京大学

Adhesiolysis and targeted steroid/local anesthetic injection during epiduroscopy alleviates pain and reduces sensory nerve dysfunction in patients with chronic sciatica.

PURPOSE: The aim of this study was to evaluate the effect of adhesiolysis followed by the injection of steroid and local anesthetic during epiduroscopy on sensory nerve function, pain, and functional disability in patients with chronic sciatica. METHODS: Epidural adhesiolysis, using epiduroscopy, followed by the injection of steroid and local anesthetic, was scheduled in 19 patients with chronic sciatica refractory to lumbar epidural block. Sensory nerve function in the legs was tested with a series of 2000-Hz (Abeta-fiber), 250-Hz (Adelta-fiber), and 5-Hz (C-fiber) stimuli, using the current perception threshold (CPT), and CPT values and intensity of pain and Roland Morris Disability Questionnaire (RMDQ) scores were assessed before and 1 and 3 months after the epiduroscopy. RESULTS: At all frequencies, the CPT values in the affected legs of patients before the epiduroscopy were significantly higher than those in the unaffected legs. Epidural adhesiolysis was successfully performed in 16 of the 19 patients. In these patients, the CPT values at 2000 and 250 Hz, and the pain and RMDQ scores 1 and 3 months after the epiduroscopy were significantly lower than those before the epiduroscopy, while the CPT value at 5 Hz did change. CONCLUSION: Epidural adhesiolysis followed by the injection of steroid and local anesthetic during epiduroscopy alleviated pain, and functional disability, and reduced dysfunction of Abeta and Adelta fibers in patients with chronic sciatica

Essential anatomy for lateral lymph node dissection

In Western countries, the gold-standard therapeutic strategy for rectal cancer is preoperative chemoradiotherapy (CRT) following total mesorectal excision (TME), without lateral lymph node dissection (LLND). However, preoperative CRT has recently been reported to be insufficient to control lateral lymph node recurrence in cases of enlarged lateral lymph nodes before CRT, and LLND is considered necessary in such cases. We performed a literature review on aspects of pelvic anatomy associated with rectal surgery and LLND, and then combined this information with our experience and knowledge of pelvic anatomy. In this review, drawing upon research using a 3-dimensional anatomical model and actual operative views, we aimed to clarify the essential anatomy for LLND. The LLND procedure was developed in Asian countries and can now be safely performed in terms of functional preservation. Nonetheless, the longer operative time, hemorrhage, and higher complication rates with TME accompanied by LLND than with TME alone indicate that LLND is still a challenging procedure. Laparoscopic or robotic LLND has been shown to be useful and is widely performed; however, without a sufficient understanding of anatomical landmarks, misrecognition of vessels and nerves often occurs. To perform safe and accurate LLND, understanding the landmarks of LLND is essential

Application of carbon dioxide to the skin and muscle oxygenation of human lower-limb muscle sites during cold water immersion

Background Cold therapy has the disadvantage of inducing vasoconstriction in arterial and venous capillaries. The effects of carbon dioxide (CO2) hot water depend mainly on not only cutaneous vasodilation but also muscle vasodilation. We examined the effects of artificial CO2 cold water immersion (CCWI) on skin oxygenation and muscle oxygenation and the immersed skin temperature. Subjects and Methods Fifteen healthy young males participated. CO2-rich water containing CO2 >1,150 ppm was prepared using a micro-bubble device. Each subject’s single leg was immersed up to the knee in the CO2-rich water (20 °C) for 15 min, followed by a 20-min recovery period. As a control study, a leg of the subject was immersed in cold tap-water at 20 °C (CWI). The skin temperature at the lower leg under water immersion (Tsk-WI) and the subject’s thermal sensation at the immersed and non-immersed lower legs were measured throughout the experiment. We simultaneously measured the relative changes of local muscle oxygenation/deoxygenation compared to the basal values (Δoxy[Hb+Mb], Δdeoxy[Hb+Mb], and Δtotal[Hb+Mb]) at rest, which reflected the blood flow in the muscle, and we measured the tissue O2 saturation (StO2) by near-infrared spectroscopy on two regions of the tibialis anterior (TA) and gastrocnemius (GAS) muscles. Results Compared to the CWI results, the Δoxy[Hb+Mb] and Δtotal[Hb+Mb] in the TA muscle at CCWI were increased and continued at a steady state during the recovery period. In GAS muscle, the Δtotal[Hb+Mb] and Δdeoxy[Hb+Mb] were increased during CCWI compared to CWI. Notably, StO2values in both TA and GAS muscles were significantly increased during CCWI compared to CWI. In addition, compared to the CWI, a significant decrease in Tsk at the immersed leg after the CCWI was maintained until the end of the 20-min recovery, and the significant reduction continued. Discussion The combination of CO2 and cold water can induce both more increased blood inflow into muscles and volume-related (total heme concentration) changes in deoxy[Hb+Mb] during the recovery period. The Tsk-WI stayed lower with the CCWI compared to the CWI, as it is associated with vasodilation by CO2

Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection

During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer EBAB (Bub1-Acoxl-Bim), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, EBAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, EBAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate EBAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling

Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase

がんによって全身に不調が生じるのはなぜか? --がんをもつ個体の肝臓の異常に焦点をあてる--. 京都大学プレスリリース. 2022-06-16.Cancers disrupt host homeostasis in various manners but the identity of host factors underlying such disruption remains largely unknown. Here we show that nicotinamide-N-methyltransferase (NNMT) is a host factor that mediates metabolic dysfunction in the livers of cancer-bearing mice. Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver. Multi-omics analyses reveal suppression of the urea cycle accompanied by accumulation of amino acids, and enhancement of uracil biogenesis in the livers of cancer-bearing mice. Importantly, genetic deletion of Nnmt leads to alleviation of these metabolic abnormalities, and buffers cancer-dependent weight loss and reduction of the voluntary wheel-running activity. Our data also demonstrate that MNAM is capable of affecting urea cycle metabolites in the liver. These results suggest that cancers up-regulate the hepatic NNMT pathway to rewire liver metabolism towards uracil biogenesis rather than nitrogen disposal via the urea cycle, thereby disrupting host homeostasis