Publications by authors named "Rui Sato"

23 Publications

  • Page 1 of 1

Real-world outcomes of molecular targeted agents for patients with hepatocellular carcinoma over 80 years old.

Hepatol Res 2022 Aug 3. Epub 2022 Aug 3.

Division of Interventional Radiology, Shizuoka Cancer Center, Sunto-Gun, Japan.

Aim: There is insufficient evidence regarding the safety and efficacy of molecular targeted agents (MTAs) for elderly patients with hepatocellular carcinoma (HCC), who are likely to be vulnerable to adverse events (AEs) of therapy. The aim of this study was to compare sorafenib and lenvatinib use in elderly patients with HCC from the viewpoint of overall survival (OS) and rate of AE-induced MTA discontinuation.

Methods: This retrospective study included patients with HCC over 80 years old who received first-line molecular targeted therapy (MTT) at four hospitals between June 2009 and September 2019. They were divided into three groups according to the era and type of first-line MTA: E1-Sora (sorafenib, between 2009 and 2016), E2-Sora (sorafenib, between 2017 and 2019), and E2-Len (lenvatinib, between 2017 and 2019).

Results: The study included 173 patients (E1-Sora, n = 79; E2-Sora, n = 50; E2-Len, n = 44) with a median age of 81.9 years (range, 80-93 years). Median OS was 15.1 months in the entire cohort (E1-Sora, 12.7 months; E2-Sora, 20.5 months; E2-Len, 10.3 months). The rate of treatment discontinuation due to AEs was high in the entire cohort, especially in E1-Sora and E2-Len (49.4% in E1-Sora, 28.0% in E2-Sora, and 54.6% in E2-Len, p = 0.0753). More E2-Sora patients received subsequent MTT than E2-Len patients (E2-Sora, 50%; E2-Len, 28.6%; p = 0.0111).

Conclusion: Both sorafenib and lenvatinib were effective and feasible for elderly patients with HCC. In terms of discontinuation due to AEs and subsequent MTT, sorafenib might be more desirable for elderly patients with HCC over 80 years.
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http://dx.doi.org/10.1111/hepr.13818DOI Listing
August 2022

Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2022 Jan 6;11(1):48-60. Epub 2021 Dec 6.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background And Aims: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet.

Approach And Results: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, = 267; period 2: 2013-2016, = 352; period 3: 2017-2019, = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively ( = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC.

Conclusions: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.
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http://dx.doi.org/10.1159/000519868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820147PMC
January 2022

Hepatitis C virus eradication prolongs overall survival in hepatocellular carcinoma patients receiving molecular-targeted agents.

J Gastroenterol 2022 02 15;57(2):90-98. Epub 2022 Jan 15.

Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.

Background: The aim of this multicenter retrospective study was to evaluate the impact of the eradication of hepatitis C virus (HCV) on the clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with molecular-targeted agents (MTAs).

Methods: Among 877 patients who received any MTA as first-line systemic therapy for HCC between June 2009 and March 2019, 569 patients with HCV-related HCC were enrolled in this retrospective study. Of these, 109 patients achieved sustained virological response (SVR) before starting MTA. After propensity score matching, the clinical outcomes of 109 patients in the SVR group and 109 patients in the non-SVR group were compared.

Results: The median time to progression in the SVR group (7.8 months) was similar to that in the non-SVR group (5.6 months) (p = 0.212). The median time to treatment failure in the SVR group (5.3 months) was longer than that in the non-SVR group (2.8 months) (p = 0.059), and post-progression survival and overall survival in the SVR group were significantly longer than those in the non-SVR group (12.0 months vs 7.2 months; p = 0.039, and 18.1 months vs 11.3 months; p = 0.019). At the end of first-line MTA therapy, the albumin-bilirubin (ALBI) score in the SVR group ( - 2.25) was significantly lower than that in the non-SVR group ( - 2.10) (p = 0.008).

Conclusions: The eradication of HCV before MTA therapy maintained liver function and led to a prolonged treatment period and improved overall survival of HCV-related HCC patients. We should not overlook the benefits of HCV eradication in HCC patients.
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http://dx.doi.org/10.1007/s00535-021-01837-5DOI Listing
February 2022

Cortical signature related to psychometric properties of pain vigilance in healthy individuals: A voxel-based morphometric study.

Neurosci Lett 2022 02 7;772:136445. Epub 2022 Jan 7.

Institute for Human Movement and Medical Sciences, Niigata University of Health and Welfare, 1398 Shimami-cho, Kita-Ku, Niigata-City, Niigata 950-3198, Japan; Department of Physical Therapy, Niigata University of Health and Welfare, Niigata City, Niigata 950-3198, Japan. Electronic address:

The Pain Vigilance and Awareness Questionnaire (PVAQ) is a questionnaire for non-clinical and clinical cases of patients, such as those suffering from chronic pain. Moreover, it is used for evaluation of two aspects of habitual attention to pain: attention to pain and attention to changes in pain. As the PVAQ assesses two different aspects of attention function, different neural basis may present. However, it remains unclear which brain regions are involved. Here, we performed voxel-based morphometry (VBM) in 30 healthy participants to determine the regional morphology associated with the two attention states. Multiple regression analysis was conducted between each score and the regional grey matter (GM) volume, which revealed that a decreased GM volume in the left anterior insular cortex (AIC) was associated with a higher attention to pain score. In contrast, no brain region was correlated with the attention to changes in pain score. Our VBM results demonstrate that attention to pain scores assessed by PVAQ are associated with morphological features of the left AIC. Moreover, they may contribute to the elucidation of the complex psychological and neurophysiological characteristics of patients with chronic pain.
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http://dx.doi.org/10.1016/j.neulet.2022.136445DOI Listing
February 2022

Prognostic impact of abutment to the branches of the superior mesenteric artery in borderline resectable pancreatic cancer.

Langenbecks Arch Surg 2020 Nov 27;405(7):939-947. Epub 2020 Aug 27.

Divisions of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan.

Purpose: The clinical impact of abutment to an artery and its branch on resectability and prognosis in patients with borderline resectable pancreatic cancer is unclear.

Methods: Patients diagnosed with borderline resectable pancreatic cancer due to artery abutment between April 2012 and December 2018 were enrolled. Contact between arteries and the tumour was assessed by computed tomography (CT).

Results: A primary lesion was resected in 63 patients (R group) and unresected in 19 patients (UR group). Overall survival (OS) was worse in the UR group than in the R group (P < 0.001). Multivariate analysis showed that abutment to the superior mesenteric artery (SMA) branches (P = 0.001) was an independent predictor of poor OS after surgery. Regarding the initial recurrence pattern, abutment to the SMA branches was significantly associated with high incidence of distant metastasis (P < 0.001). According to the most distal SMA branch attached on CT, significant differences in RFS were found between absent-J1A (P = 0.017), J2A-J3A (P = 0.0313) and J3A-middle colic artery (MCA, P = 0.0476) but not between J1A-J2A (P = 0.8207). Significant prognostic differences in OS after initiation of the treatment were found between absent-J1A/J2A (P = 0.006) and J1A/J2A-J3A/MCA (P = 0.033) but not between J3A/MCA-UR (P = 0.494).

Conclusion: Abutment to the SMA branches was associated with high incidence of distant metastasis after resection and a poor survival. Especially, abutment to the J3A or MCA was associated with poor prognosis comparable with that of the UR group.
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http://dx.doi.org/10.1007/s00423-020-01970-4DOI Listing
November 2020

AS3288802, a highly selective antibody to active plasminogen activator inhibitor-1 (PAI-1), exhibits long efficacy duration in cynomolgus monkeys.

Biologicals 2020 Sep 20;67:21-28. Epub 2020 Aug 20.

Astellas Innovation Management LLC, 1030 Massachusetts Avenue, Cambridge, MA, 02138, United States. Electronic address:

Antibodies have strong affinity to their target molecules, a characteristic that is utilized in antibody drugs. For antibody drugs, target molecule specificity and long duration pharmacokinetics, along with strong affinity to the target molecule are important characteristics. Plasminogen activator inhibitor-1 (PAI-1) is one of the key regulators of the fibrinolysis system, and the benefits of PAI-1 activity inhibition have been widely reported for multiple thrombosis and fibrosis-related diseases. Here, we generated a novel antibody, AS3288802, with high selectivity for active PAI-1. AS3288802 exhibited prolonged and strong inhibition of PAI-1 activity in cynomolgus monkey blood in vivo. Given that AS3288802 showed prolonged antigen inhibition activity due to its high target molecule selectivity, we propose that increasing target molecule selectivity may be a key strategy for lengthening the efficacy duration of antibody drugs. AS3288802 may be a promising anti-PAI-1 antibody drug with multiple clinical applications including thrombosis and fibrosis-related diseases.
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http://dx.doi.org/10.1016/j.biologicals.2020.08.001DOI Listing
September 2020

Intrahepatic Tumor Burden as a Novel Factor Influencing the Introduction of Second-line Chemotherapy for Hepatocellular Carcinoma.

Anticancer Res 2020 Jul;40(7):3953-3960

Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background/aim: To examine the factors influencing the introduction of the second-line chemotherapy and discuss the selection of first-line agent for hepatocellular carcinoma (HCC).

Patients And Methods: We retrospectively studied 154 patients with HCC who received sorafenib therapy.

Results: A total of 109 (70.8%) patients, maintained Child-Pugh grade A and Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 upon sorafenib discontinuation. Multivariate analysis revealed that the up-to-seven criteria status in the hepatic lesion [p=0.019; odds ratio=OR, 2.685], albumin-bilirubin (ALBI) grade (p=0.002; OR=3.589), and macroscopic vascular invasion (MVI) (p=0.008; OR=2.972) were significant factors at sorafenib initiation that influenced the maintenance of Child-Pugh grade A and ECOG-PS ≤1 upon therapy discontinuation.

Conclusion: Not only ALBI grade and MVI, but also up-to-seven criteria status in the hepatic lesion influence the introduction of second-line therapy, and could affect the selection of the first-line therapy.
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http://dx.doi.org/10.21873/anticanres.14387DOI Listing
July 2020

A randomized, controlled trial of the efficacy of percutaneous transesophageal gastro-tubing (PTEG) as palliative care for patients with malignant bowel obstruction: the JIVROSG0805 trial.

Support Care Cancer 2020 Jun 7;28(6):2563-2569. Epub 2019 Sep 7.

Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.

Background: A randomized, controlled trial to evaluate the superiority of percutaneous transesophageal gastro-tubing over nasogastric tubing as palliative care for bowel obstruction in patients with terminal malignancy was conducted.

Subjects And Methods: The subjects were patients with malignant bowel obstruction with no prospect of improvement, for whom surgery was not indicated and with a Palliative Prognostic Index of < 6. They were randomly allocated in a 1:1 ratio to receive either percutaneous transesophageal gastro-tubing (PTEG group) or nasogastric tubing (NGT group). Their symptom scores (the worst 0 to no symptoms 10) were measured for a 2-week period after enrollment, and the areas under the curves for the two groups were compared. The EQ-5D and SF-8 were also used to assess overall quality of life.

Results: Forty patients were enrolled between October 2009 and January 2015, with 21 allocated to the PTEG group and 19 to the NGT group. The mean areas under the curves (95% confidence intervals) for the PTEG group and the NGT groups were 149.6 (120.3-178.8) and 44.9 (16.4-73.5), respectively, significantly higher for the NGT group (p < 0.0001). The secondary endpoints of quality of life as assessed by the EQ-5D and SF-8 scores were also significantly higher for patients in the PTEG group (p = 0.0036, p = 0.0020). There was no difference in survival between the groups. No serious adverse events were observed.

Conclusions: In terms of quality of life, percutaneous transesophageal gastro-tubing was superior to nasogastric tubing as palliative care for patients with bowel obstruction due to terminal malignancy.
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http://dx.doi.org/10.1007/s00520-019-05066-8DOI Listing
June 2020

Phase II Trial of Transarterial Embolization Using an n-Butyl-2-Cyanoacrylate/Lipiodol Mixture (JIVROSG-0802).

Cardiovasc Intervent Radiol 2019 Apr 6;42(4):534-541. Epub 2018 Dec 6.

Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.

Purpose: To evaluate the embolic effect and the safety of transarterial embolization (TAE) using n-butyl-2-cyanoacrylate (NBCA) in a prospective multicenter trial.

Materials And Methods: This study was an open-label, multicenter, phase II trial. The inclusion criteria were (1) active bleeding or pseudoaneurysm, (2) true aneurysm, (3) arteriovenous malformation (except cerebral lesion), (4) arteriovenous fistula, or (5) need for arterial distribution before transarterial treatment. Selective TAE with NBCA diluted 2-10 times was performed. The primary endpoint was the success rate of embolization with a per-patient analysis based on the angiographic findings. Secondary endpoints were safety, evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) version 4, and the success rate of embolization with a per-vessel calculation.

Results: Sixty-five patients were initially enrolled, but due to protocol violation in two patients, efficacy was ultimately analyzed in 63 patients (103 vessels) and safety was analyzed in 64 patients. The success rate per patient was 98.4% (62/63; 95% confidence interval (CI), 91.5-100.00), and the success rate per vessel was 99.0% (102/103; 95% CI, 94.7-100.0). Adverse events of grade 3 or above based on CTCAE version 4 occurred in 22/64 patients (34.4%). Twelve intraoperative or postoperative adverse events grade 3 or above, which may have been related to embolization using NBCA, occurred in 11/64 patients (17.2%). Three patients died after embolization using NBCA, but their deaths were unrelated to TAE.

Conclusion: In this prospective multicenter clinical trial, the efficacy of TAE using NBCA was 98.4% and adverse events were clinically acceptable.

Level Of Evidence: Level 3b.
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http://dx.doi.org/10.1007/s00270-018-2141-7DOI Listing
April 2019

Evaluation of stent placement for vena cava syndrome: phase II trial and phase III randomized controlled trial.

Support Care Cancer 2019 Mar 15;27(3):1081-1088. Epub 2018 Aug 15.

Department of Diagnostic and Interventional Radiology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan.

Purpose: Vena cava syndrome (VCS) from stenosis of the superior vena cava or inferior vena cava caused by compression from a malignant tumor is one of the typical clinical conditions in patients with advanced stage malignant disease. VCS is difficult to manage and painful, reducing patients' quality of life. Although several reports have investigated stent placement for VCS, this treatment has never been established as the standard because of the lack of evidence of the safety and efficacy. We conducted a phase II trial and a phase III randomized controlled trial to clarify the role of stent placement in managing patients with VCS.

Methods: In the phase II trial, 28 eligible patients were treated with stent placement. The efficacy of stent placement for VCS was evaluated based on the reduction of patients' symptom scores during 14 days following treatment. Technical success, technical feasibility, overall survival, recurrence of symptoms, and adverse events were evaluated. In the phase III trial, 32 patients were enrolled and randomly assigned to the test (n = 16) and control groups (n = 16). The area under the symptom score curve was compared between the groups. The EQ-5D, SF-8, and adverse events were evaluated until discontinuation of the protocol treatment or 28 days after enrollment.

Results: In the phase II trial, the median patients' symptom scores significantly decreased from 10.50 before the procedure to 3.00 after the procedure. Technical success and technical feasibility rates were 96.4% and 100%, respectively. The incidence of treatment-related grade 3 or higher adverse events was 14.3%. In the phase III trial, significant superiority of stent placement was observed in the test, compared to that in the control, group. There was no significant difference in most other evaluations between the groups.

Conclusions: Stent placement significantly improved the symptoms of VCS; thus, it might be accepted as the standard treatment to manage the symptoms of VCS.

Trial Registration: JIVROSG-0402, JIVROSG-0807.
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http://dx.doi.org/10.1007/s00520-018-4397-5DOI Listing
March 2019

Sorafenib versus Hepatic Arterial Infusion Chemotherapy as Initial Treatment for Hepatocellular Carcinoma with Advanced Portal Vein Tumor Thrombosis.

Liver Cancer 2017 Nov 29;6(4):275-286. Epub 2017 Aug 29.

Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.

Objective: To investigate the validity of hepatic arterial infusion chemotherapy with low-dose 5-fluorouracil and cisplatin (LFP) versus sorafenib as first-line treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (Vp3, Vp4).

Patients And Methods: We retrospectively reviewed the cases of Child-Pugh A advanced HCC with Vp3 or Vp4 treated with LFP or sorafenib between October 2002 and December 2013.

Results: There were 32 patients in the LFP group and 14 patients in the sorafenib group. The objective response rate/disease control rate was 31.3/56.3% in the LFP group and 0/28.6% in the sorafenib group. The median survival time (MST) (309 vs. 120 days; = 0.009) and the median time to treatment failure (109 vs. 37 days; = 0.022) were significantly longer in the LFP group than in the sorafenib group. In the LFP group, a relatively favorable outcome (MST, 622 days) was obtained among the response cases. Among the nonresponse cases in the LFP group, at the time of cessation of LFP, 70.4% of cases were Child-Pugh A and 88.9% of cases maintained a score of ≤7 points; of the cases in whom Child-Pugh A was maintained, the survival period from the time of LFP discontinuation was significantly longer in the cases in whom sorafenib was introduced as a secondary treatment after LFP than in the cases treated with best supportive care (220 vs. 89 days; = 0.002). The main adverse event with LFP was grade 3 or higher cytopenia, which was manageable, and adverse event-induced discontinuation was significantly lower as compared with sorafenib ( = 0.002).

Conclusion: For the treatment of HCC with Vp3/Vp4, it is desirable to initially use LFP and then immediately change to sorafenib if no response is obtained.
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http://dx.doi.org/10.1159/000473887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704700PMC
November 2017

"Direct MPR": A Useful Tool for Oblique CT Fluoroscopy-Assisted Puncture.

Cardiovasc Intervent Radiol 2017 Aug 24;40(8):1261-1266. Epub 2017 Apr 24.

Division of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka, Japan.

Objective: Conventional multiplanar reconstruction (MPR) imaging can be used as a tool for planning oblique puncture procedures, but it takes a few minutes to reconstruct and is not appropriate for real-time CT fluoroscopy-assisted puncture. Recently, new MPR technology has been used that requires only 8 s and makes it possible to obtain a nearly real-time CT fluoroscopy-assisted oblique puncture. We refer to it as "direct MPR." This is the first clinical report of this technique.

Methods: Since February 2016, we have performed real-time, CT-guided oblique punctures with this new technology, "direct MPR," using an angio-CT system. We retrospectively reviewed all of our procedures with this new method between February 2016 and June 2016.

Results: We used this technique for 14 cases during the study period. Eight cases were radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC), four were biopsies (lung and adrenal gland), and two were for percutaneous abscess drainage. Six of eight RFA cases were for HCC located immediately below the diaphragm. Both of the drainage cases were abscesses located immediately below the diaphragm. All procedures were successfully completed. The average length of the lesion in the RFA cases was 15.4 ± 3.2 mm. The average length of the lesions in all of the cases was 30.9 ± 31.9 mm. The average craniocaudal angle was 32.5° ± 14.0°.

Conclusions: Direct MPR makes CT-guided oblique puncture for inaccessible targets, especially those located immediately below diaphragm, easier and safer.

Level Of Evidence: Case series, Level IV.
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http://dx.doi.org/10.1007/s00270-017-1642-0DOI Listing
August 2017

Corticosteroid and progesterone transactivation of mineralocorticoid receptors from Amur sturgeon and tropical gar.

Biochem J 2016 Oct 12;473(20):3655-3665. Epub 2016 Aug 12.

Graduate School of Life Science, Hokkaido University, Sapporo, Japan Department of Biological Sciences, Hokkaido University, Sapporo, Japan.

The response to a panel of steroids by the mineralocorticoid receptor (MR) from Amur sturgeon and tropical gar, two basal ray-finned fish, expressed in HEK293 cells was investigated. Half-maximal responses (EC50s) for transcriptional activation of sturgeon MR by 11-deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol and aldosterone, and progesterone (Prog) were between 13 and 150 pM. For gar MR, EC50s were between 8 and 55 pM. Such low EC50s support physiological regulation by these steroids of the MR in sturgeon and gar. Companion studies with human and zebrafish MRs found higher EC50s compared with EC50s for sturgeon and gar MRs, with EC50s for zebrafish MR closer to gar and sturgeon MRs than was human MR. For zebrafish MR, EC50s were between 75 and 740 pM; for human MR, EC50s were between 65 pM and 2 nM. In addition to Prog, spironolactone (spiron) and 19nor-progesterone (19norP) were agonists for all three fish MRs, in contrast with their antagonist activity for human MR, which is hypothesized to involve serine-810 in human MR because all three steroids are agonists for a mutant human Ser810Leu-MR. Paradoxically, sturgeon, gar, and zebrafish MRs contain a serine corresponding to serine-810 in human MR. Our data suggest alternative mechanism(s) for Prog, spiron, and 19norP as MR agonists in these three ray-finned fishes and the need for caution in applying data for Prog signaling in zebrafish to human physiology.
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http://dx.doi.org/10.1042/BCJ20160579DOI Listing
October 2016

A second estrogen receptor from Japanese lamprey (Lethenteron japonicum) does not have activities for estrogen binding and transcription.

Gen Comp Endocrinol 2016 09 16;236:105-114. Epub 2016 Jul 16.

Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, Japan; National Institute for Basic Biology, Okazaki, Japan. Electronic address:

Estrogens regulate many physiological responses in vertebrates by binding to the estrogen receptor (ER), a ligand-activated transcription factor. To understand the evolution of vertebrate ERs and to investigate how estrogen acts in a jawless vertebrate, we used degenerate primer sets and PCR to isolate DNA fragments encoding two distinct ER subtypes, Esr1a and Esr1b from the Japanese lamprey, Lethenteron japonicum. Phylogenetic analysis indicates that these two ERs are the result of lineage-specific gene duplication within the jawless fishes, different from the previous duplication event of Esr1 (ERα) and Esr2 (ERβ) within the jawed vertebrates. Reporter gene assays show that lamprey Esr1a displays both constitutive and estrogen-dependent activation of gene transcription. Domain swapping experiments indicate that constitutive activity resides in the A/B domain of lamprey Esr1a. Unexpectedly, lamprey Esr1b does not bind estradiol and is not stimulated by other estrogens, androgens or corticosteroids. A 3D model of lamprey Esr1b suggests that although estradiol fits into the steroid binding site, some stabilizing contacts between the ligand and side chains that are found in human Esr1 and Esr2 are missing in lamprey Esr1b.
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http://dx.doi.org/10.1016/j.ygcen.2016.07.014DOI Listing
September 2016

Erratum to: Effects of preoperative and intraoperative glucose administration on glucose use and fat catabolism during laparotomy under sevoflurane anesthesia in fasted rats.

J Physiol Sci 2015 Nov;65(6):531

Department of Anesthesiology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

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http://dx.doi.org/10.1007/s12576-015-0406-3DOI Listing
November 2015

Effects of preoperative and intraoperative glucose administration on glucose use and fat catabolism during laparotomy under sevoflurane anesthesia in fasted rats.

J Physiol Sci 2015 Nov 18;65(6):523-30. Epub 2015 Aug 18.

Department of Anesthesiology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Preoperative fasting as well as surgical stress significantly modifies metabolisms. Recent studies reported the possible advantageous effects of glucose administration on perioperative metabolisms; however, the underlying mechanisms have not been fully elucidated. Rats were allocated to three groups. During the fasting period, groups A and B were administered water, but group C was administered glucose. During laparotomy and the insulin tolerance test (ITT) under sevoflurane anesthesia, group A was administered saline, but groups B and C were administered glucose. During laparotomy, group C showed higher glucose levels and lower β-hydroxybutyrate (β-OHB) levels than group A, and group B showed more decreases in β-OHB levels than group A without differences in changes in glucose levels. Insulin levels and insulin sensitivity during laparotomy were similar among the three groups. No significant difference in insulin sensitivity was also confirmed in ITT. In conclusion, perioperative glucose administration suppresses lipolysis without affecting insulin secretion and sensitivity.
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http://dx.doi.org/10.1007/s12576-015-0390-7DOI Listing
November 2015

Comparison of mechanisms underlying changes in glucose utilization in fasted rats anesthetized with propofol or sevoflurane: Hyperinsulinemia is exaggerated by propofol with concomitant insulin resistance induced by an acute lipid load.

Biosci Trends 2014 Jun;8(3):155-62

Department of Anesthesiology, Graduate School of Medicine, The University of Tokyo.

The effects of anesthesia with sevoflurane and with propofol on glucose utilization in rats were investigated. Sevoflurane significantly impairs glucose utilization whereas propofol does not. Both insulin secretion and sensitivity affect glucose utilization. Propofol is hydrophobic, and anesthesia with this agent is always accompanied by an acute lipid load, which can exaggerate insulin resistance. The role of the acute lipid load in the effects of anesthesia with sevoflurane and propofol on glucose utilization in fasted rats was investigated. Rats were allocated to groups anesthetized with sevoflurane and infused with physiological saline (group S) or 10% w/v lipid (group SL), or those anesthetized with propofol (group P). Intravenous glucose tolerance tests and insulin tolerance tests were then performed to measure glucose utilization, and blood glucose, plasma insulin, and plasma TNF-α levels were measured. In the intravenous glucose tolerance test, groups SL and P showed significantly higher plasma insulin levels than group S, and group P showed significantly higher plasma insulin levels than group SL. In the insulin tolerance test, groups SL and P showed insulin resistance compared to group S, but no significant difference was observed between groups SL and P. In summary, propofol anesthesia enhances insulin secretion and concomitantly exaggerates insulin resistance, compared with sevoflurane anesthesia. Propofol appears to be the main cause of hyperinsulinemia, and the acute lipid load exaggerates insulin resistance.
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http://dx.doi.org/10.5582/bst.2014.01060DOI Listing
June 2014

Ectopic localization of auxin and cytokinin in tobacco seedlings by the plant-oncogenic AK-6b gene of Agrobacterium tumefaciens AKE10.

Planta 2013 Oct 20;238(4):753-70. Epub 2013 Jul 20.

Department of Biological Production, Faculty of Bioresource Sciences, Akita Prefectural University, 241-438 Kaidobata Nishi, Nakano-Aza, Shimoshinjo, Akita, 010-0195, Japan.

The oncogenic 6b gene of Agrobacterium tumefaciens induces a number of morphological and metabolic alterations in plants. Although molecular functions associated with the 6b genes have been proposed, including auxin transport, sugar transport, transcriptional regulation, and miRNA metabolism, so far an unequivocal conclusion has not been obtained. We investigated the association between auxin accumulation and tumor development of the tobacco seedlings expressing the AK-6b gene under the control of the dexamethasone-inducible promoter. Indole-3-acetic acid (IAA) localization was examined by immunochemical staining with monoclonal antibody against IAA and by histochemical analysis using the IAA-specific induced construct, DR5::GUS (β-glucuronidase). Both procedures indicated that IAA preferentially accumulated in the tumorous protrusions as well as in newly developing vascular bundles in the tumors. Furthermore, true leaves also showed abaxial IAA localization, leading to altered leaves in which the adaxial and abaxial identities were no longer evident. Co-localization of cytokinin and auxin in the abaxial tumors was verified by immunochemical staining with an antibody against cytokinin. Treatment of AK-6b-seedlings with N-1-naphthylphthalamic acid, an inhibitor of polar auxin transport, promoted the morphological severity of phenotypes, whereas 1-naphthoxyacetic acid, a specific auxin influx carrier inhibitor, induced tumor regression on cotyledons and new tumorous proliferations on hypocotyls. Prominent accumulation of both auxin and cytokinin was observed in both regressed and newly developing tumors. We suggest from these results that modulation of auxin/cytokinin localization as a result of AK-6b gene expression is responsible for the tumorous proliferation.
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http://dx.doi.org/10.1007/s00425-013-1930-0DOI Listing
October 2013

Glucose use in fasted rats under sevoflurane anesthesia and propofol anesthesia.

Anesth Analg 2013 Sep 18;117(3):627-633. Epub 2013 Jul 18.

From the Department of Anesthesiology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

Background: We previously reported the marked differences in the effects of sevoflurane anesthesia and propofol anesthesia on glucose use in fed rats; however, we could not elucidate mechanisms underlying the differences.

Methods: We used fasted rats in this study. After surgical preparation under sevoflurane anesthesia, rats were divided into 3 groups: awake rats, rats under sevoflurane anesthesia, and rats under propofol anesthesia. All rats underwent the IV glucose tolerance test (IVGTT); 0.5 g/kg glucose was administered IV to rats. Just before IVGTT, some rats were pretreated with glibenclamide or diazoxide. We measured glucose, insulin, tumor necrosis factor-α (TNF-α), and high molecular weight adiponectin levels during IVGTT and calculated the quantitative insulin sensitivity check index (QUICKI) using glucose and insulin levels before glucose administration in each rat.

Results: Before glucose administration, rats under sevoflurane anesthesia showed similar glucose and insulin levels with significantly higher QUICKI compared with awake rats, while rats under propofol anesthesia showed similar glucose levels and significantly higher insulin levels with significantly lower QUICKI compared with awake rats. After glucose administration, rats under sevoflurane anesthesia showed significantly higher glucose levels and similar insulin levels compared with awake rats, while rats under propofol anesthesia showed similar glucose levels and significantly higher insulin levels compared with awake rats. Before glucose administration, TNF-α levels in rats under sevoflurane anesthesia and rats under propofol anesthesia were similar to those in awake rats. After glucose administration, TNF-α was undetectable in all awake rats and all rats under sevoflurane anesthesia, whereas TNF-α was detectable in all rats under propofol anesthesia; TNF-α levels in rats under propofol anesthesia were significantly higher than those in awake rats. High molecular weight adiponectin levels in rats under sevoflurane anesthesia and rats under propofol anesthesia were similar to those in awake rats throughout the experimental period. In rats under sevoflurane anesthesia, glibenclamide significantly decreased glucose levels and significantly increased insulin levels; however, diazoxide produced no significant effects on glucose and insulin levels. In rats under propofol anesthesia, glibenclamide significantly decreased glucose levels and significantly increased insulin levels, while diazoxide significantly decreased glucose levels without changing insulin levels.

Conclusions: Sevoflurane anesthesia attenuates glucose-induced insulin secretion without affecting basic insulin secretion, while propofol anesthesia enhances insulin secretion. Propofol anesthesia exaggerates insulin-resistive conditions, whereas sevoflurane anesthesia dose not impair insulin sensitivity; there may be a possible association of TNF-α with insulin-resistive conditions under propofol anesthesia.
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http://dx.doi.org/10.1213/ANE.0b013e31829e4028DOI Listing
September 2013

Glucose administration during volume resuscitation using dextran-40 from hemorrhagic shock ameliorates acid/base-imbalance in fasted rats under sevoflurane anesthesia.

Biosci Trends 2013 Jun;7(3):138-43

Department of Anesthesiology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

The hyperglycemic response is an important prognostic factor for survival after hemorrhage. In this study, we investigated the effects of glucose administration during volume resuscitation from hemmorhagic shock in fasted rats under sevoflurane anesthesia on hemodynamics, acid/base-balance and glucose metabolism. Hemorrhagic shock was induced in rats by withdrawing 25 mL/kg of blood. For volume resuscitation, rats in group-Dextran[saline] and group-Dextran[glucose] underwent infusion therapy using 10% dextran-40 dissolved in physiological saline and 10% dextran-40 dissolved in 5% glucose, respectively. Arterial blood was sampled just before blood withdrawal, immediately after blood withdrawal, immediately after volume resuscitation and at 30 min after volume resuscitation for arterial gas analyses and measurement of plasma insulin levels. After volume resuscitation, group-Dextran[glucose] showed similar arterial blood pressure, significantly lower heart rate, similar arterial PO₂ and similar hematocrit in comparison with group-Dextran[saline], suggesting that there was no particular difference in oxygen demand/supply-balance between the two groups. After volume resuscitation, group-Dextran[glucose] showed significantly higher arterial pH, similar arterial PCO₂, significantly higher bicarbonate levels and significantly higher base excess in comparison with group-Dextran[saline], suggesting that metabolic acidosis is a cause of the difference in acid/ base-balance between the two groups. After volume resuscitation, group-Dextran[glucose] showed significantly higher glucose levels, significantly higher insulin levels and significantly lower lactate levels in comparison with group-Dextran[saline]. At 30 min after volume resuscitation, base excess correlated significantly with lactate levels. These results suggest that glucose administration during volume resuscitation using dextran-40 from hemorrhagic shock ameliorates acid/base-imbalance associated with hyperlactatemia in fasted rats under sevoflurane anesthesia.
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June 2013

Comparison of the Airway Scope and Macintosh laryngoscope with in-line cervical stabilization by the semisolid neck collar: manikin study.

J Trauma 2010 Feb;68(2):363-6

Trauma and Critical Care Center, Teikyo University School of Medicine, Tokyo, Japan.

Background: The usefulness of Airway Scope (AWS) and Macintosh direct laryngoscope (ML) for patients with trauma requiring intubation with in-line cervical stabilization for protection of the cervical spine was compared.

Methods: Thirty-three residents performed orotracheal intubation using ML and AWS in an intubation model with in-line cervical stabilization. The tracheal intubation success rate, time required for tracheal intubation, and number of trials of inserting the tracheal tube into the trachea were measured in individual residents.

Results: Two residents inserted the tube into the esophagus using ML (success rate: 93.9%), but all residents succeeded in tracheal intubation using AWS (success rate: 100%) (p = 0.492). The time required for intubation was similar using AWS and ML (15 seconds vs. 20 seconds, p = 0.261). The number of trials using AWS was significantly lower (2.0 times vs. 1.0 times, p = 0.001).

Conclusion: The usefulness of AWS may be comparable with or greater than that of ML for oral intubation in trauma patients with in-line cervical stabilization.
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http://dx.doi.org/10.1097/TA.0b013e3181a70940DOI Listing
February 2010

[Anesthetic management of four patients with Fournier syndrome].

Masui 2008 Mar;57(3):355-7

Department of Anesthesiology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655.

We experienced anesthetic managements of four patients with Fournier syndrome. In the anesthetic management of the patients with Fournier syndrome the following three points should be kept in mind; (a) the necessity of careful preoperative examination, (b) the better anesthesia, and (c) the careful postoperative care.
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March 2008

[Case of catecholamine-resistant shock caused by drug overdose].

Chudoku Kenkyu 2007 Jan;20(1):59-63

Tertiary Emergency Medical Center, Saitama Red Cross Hospital.

A 27-year-old man with schizophrenia took an overdose of a psychotic agent. He became unconscious and had severe hypotension. Although he was diagnosed as having distributive shock caused by drug overdose and treated by hydration and catecholamine, the shock status was lasting. The use of vasopressin changed the situation dramatically. After the injection of vasopressin at maximum dose, 0.1 U/min, the dose of vasopressin could be tapered. He recovered from shock and was discharged on the third day without sequelae. There are an increasing number of reports that indicate that vasopressin is effective for distributive shock, especially catecholamine-resistant septic shock. It seems that the appropriate dose of vasopressin is under 0.04U/min considering the deterioration of cardiac function although the maximum dose of vasopressin was O.1U/min in this case. For that reason, monitoring by pulmonary artery catheter is recommended. The side effects of vasopressin should be discussed for appropriate use.
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January 2007
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