A whole body indirect calorimeter provides accurate measurement of energy expenditure and the respiration quotient over long periods of time, but has limitations to assess dynamic changes in energy metabolism due to the small amplitude of the signal in relation to the size of the room. The present study aimed to improve algorithm for the whole body indirect calorimetry by adopting a deconvolution with a regularization parameter. Performance of the new algorithm was compared with trends identification (Med. & Biol. Eng. & Comput 34 : 212, 1996) against four validation tests. In a simulated problem, in which metabolic rate cycled with a period of 20 min, mean square errors (MSEs) computed at every 1 min by the deconvolution (0.0036 for O₂ consumption and 0.0017 for CO₂ production) were smaller than those for trends identification algorithms (0.0198 and 0.0142). Deconvolution algorithm clearly separated individual CO₂ infusion of 8 min intervals, while trends identification could no longer separate them. During the validation by ethanol combustion, which produced a near-steady state condition, the deconvolution (MSEs were 0.0022 for O₂ consumption and 0.0010 for CO₂ production) performed better than trends identification algorithms (MSEs were 0.0086 and 0.0041). When validated against direct measurement of gas production rate during non-steady state condition, produced by a human subject intermittently exercising in the calorimeter, deconvolution (MSEs were 0.0032 for O₂ consumption and 0.0038 for CO₂ production) performed better than trends identification algorithms (0.0182 and 0.0167). The new algorithm significantly improved transient response of the whole body indirect calorimeter.

In this study, the effect of moderate endurance training on muscle morphological properties of human thigh muscles and isokinetic strength was examined. Five sedentary females carried out a training program of 30 min./day, 3 times a week for a ten-week period. The load requirement was set to 60% of maximal aerobic capacity (Vo₂max) of the subjects. In the determination of muscle cross-sectional areas (CSAs) by MRI, longitudinal sections were first imaged, and ten axial images along the length of femur were taken before and after the endurance training. Muscle CSA and mus-cle volume of knee extensors (KE), flexors (KF), and adductors (AD) were calculated, using the ten axial images. Vo₂max was significantly increased after endurance training (14.6%, p<0.01) . Muscle CSA in KE was significantly increased at the ten levels of femur length. There were also significant increases at seven levels of femur length after endurance training in KF (p<0.05, and 0.01) . Percentage increase of msucle CSA in KE and KF were 10.9 to 16.5% and 7.7 to 15.8%, respectively. Although the muscle volume of KE, KF, and AD was significantly increased, no change in fat volume was observed after endurance training. Isokinetic knee extension and flexion peak torque and peak torque per unit of muscle CSA at three angular velocities (30, 180, and 300 deg/sec) didn't show significant changes. These results suggest that muscle hypertrophy induced by moderate endurance training has no effect on muscle strength.

In this study, the effect of moderate endurance training on muscle morphological properties of human thigh muscles and isokinetic strength was examined. Five sedentary females carried out a training program of 30 min./day, 3 times a week for a ten-week period. The load requirement was set to 60% of maximal aerobic capacity (Vo₂max) of the subjects. In the determination of muscle cross-sectional areas (CSAs) by MRI, longitudinal sections were first imaged, and ten axial images along the length of femur were taken before and after the endurance training. Muscle CSA and mus-cle volume of knee extensors (KE), flexors (KF), and adductors (AD) were calculated, using the ten axial images. Vo₂max was significantly increased after endurance training (14.6%, p<0.01) . Muscle CSA in KE was significantly increased at the ten levels of femur length. There were also significant increases at seven levels of femur length after endurance training in KF (p<0.05, and 0.01) . Percentage increase of msucle CSA in KE and KF were 10.9 to 16.5% and 7.7 to 15.8%, respectively. Although the muscle volume of KE, KF, and AD was significantly increased, no change in fat volume was observed after endurance training. Isokinetic knee extension and flexion peak torque and peak torque per unit of muscle CSA at three angular velocities (30, 180, and 300 deg/sec) didn't show significant changes. These results suggest that muscle hypertrophy induced by moderate endurance training has no effect on muscle strength.

Six 1-month-old piglets were intravenously injected with deoxynivalenol (DON) at the concentration of 1 mg/kg body weight, with three pigs each necropsied at 6 and 24 h post-injection (PI) for investigation of hepatotoxicity and immunotoxicity with special attention to apoptotic changes and cytokine mRNA expression. Histopathological examination of the DON-injected pigs revealed systemic apoptosis of lymphocytes in lymphoid tissues and hepatocytes. Apoptosis of lymphocytes and hepatocytes was confirmed by the TdT-mediated dUTP-biotin nick end-labeling (TUNEL) method and immunohistochemical staining against single-stranded DNA and cleaved caspase-3. The number of TUNEL-positive cells in the thymus and Peyer's patches of the ileum was increased at 24 h PI compared to 6 h PI, but the peak was at 6 h PI in the liver. The mRNA expression of interleukin (IL)-1beta, IL-6, IL-18, and tumor necrosis factor (TNF)-alpha in the spleen, thymus and mesenteric lymph nodes were determined by semi-quantitative RT-PCR, and elevated expression of IL-1beta mRNA at 6 h PI and a decrease of IL-18 mRNA at 24 h PI were observed in the spleen. IL-1beta and IL-6 mRNA expressions increased significantly at 6 h PI in the thymus, but TNF-alpha decreased at 6 h PI in the mesenteric lymph nodes. These results show the apoptosis of hepatocytes suggesting the hepatotoxic potential of DON, in addition to an immunotoxic effect on the modulation of proinflammatory cytokine genes in lymphoid organs with extensive apoptosis of lymphocytes induced by acute exposure to DON in pigs.
Animals ; Apoptosis/*drug effects/immunology ; Cytokines/*biosynthesis/genetics ; Gene Expression Regulation/drug effects ; Histocytochemistry/veterinary ; In Situ Nick-End Labeling/veterinary ; Liver/*drug effects/immunology ; Lymphoid Tissue/*drug effects/immunology ; RNA, Messenger/*biosynthesis/genetics/immunology ; Reverse Transcriptase Polymerase Chain Reaction/veterinary ; Specific Pathogen-Free Organisms ; Swine/*immunology ; Trichothecenes/*toxicity

A Task Force team consisting of members from pharmaceutical companies --a central player to develop and implement RMP (Risk Management Plan)-- as well as health care professionals and members from academia was established in JSPE. The Task Force developed guidance for scientific approach to practical and ICH-E2E-compliant Pharmacovigilance Plan (PVP) stated in Japanese Risk Management Plan issued in April 2012 by the Ministry of Health, Labour and Welfare. The guidance contains the following topics.
1．Introduction: JSPE's activities and this task force's objectives for pharmacovigilance activities
2．How to select Safety Specification (SS) and describe its characteristics
・Selection of SS
・Characterization of SS
・Association with Research Questions (RQ)
3．How to define and describe RQ
・What is RQ ?
・RQ interpretation in other relevant guidelines
・Methodology to develop RQ for PVP with examples
・Best approach to integrating PVP for whole aspects of safety concern
4．How to optimize PVP for specific RQ
・Routine PVP or additional PVP ?
・Additional PVP design (RQ and study design, RQ structured with PICO or GPP's research objectives, specific aims, and rationale)
・Checklist to help develop PVP
5．Epilogue:
・What can/should be “Drug use investigation” in the context of ICH-E2E-compliant PVP.
・Significance of background incidence rate and needs for comparator group
・Infrastructure for the future PVP activities
6．Appendix: Checklist to help develop PVP activities in RMP
The task force team is hoping that this guidance help develop and conduct SS and PVP in accordance with ICH E2E, as stated in Japanese Risk Management Plan Guideline.

OBJECTIVE: Programmed cell death-ligand 1 (PD-L1) is expressed in tumor cells and has been shown to predict clinical outcomes of several types of malignancies. The aim of this study was to investigate the effects of carbon-ion (C-ion) beam irradiation on PD-L1 expression in human uterine cervical adeno/adenosquamous carcinoma (UCAA) cells and clinical samples and to identify the prognostic factors for outcomes after C-ion radiotherapy (CIRT).METHODS: The effects of C-ion irradiation on PD-L1 expression in human UCAA and cervical squamous cell carcinoma cells were examined by flow cytometry. We examined PD-L1 expression in UCAA biopsy specimens from 33 patients before CIRT started (pre-CIRT) and after 12 Gy (relative biological effectiveness [RBE]) irradiation (post-12Gy-C) in 4 fractions of CIRT to investigate the correlation between PD-L1 status and clinical outcomes.RESULTS: The PD-L1 expression was upregulated by C-ion beam in a dose-dependent manner in HeLa and SiHa cells through phosphorylated Chk1. The overall frequencies of pre-CIRT and post-12Gy-C PD-L1 positivity were 45% (15/33) and 67% (22/33), respectively. The post-12Gy-C PD-L1 expression was significantly elevated compared to the pre-CIRT PD-L1 expression. There was no significant relationship between the pre-CIRT PD-L1 status and clinical outcomes, such as local control (LC), progression-free survival (PFS), and overall survival (OS). However, the post-12Gy-C PD-L1 expression had better correlation with PFS, but not with LC and OS.CONCLUSION: CIRT can induce PD-L1 expression in UCAA and we propose that PD-L1 expression after starting CIRT may become as a predictive prognostic marker in CIRT for UCAA.
Antigens, CD274 ; Biopsy ; Carcinoma, Squamous Cell ; Disease-Free Survival ; Flow Cytometry ; Heavy Ion Radiotherapy ; Humans ; Radiotherapy ; Treatment Outcome ; Uterine Cervical Neoplasms

Background/Aims: Immune checkpoint blockade has recently been reported to be effective in treating microsatellite instability (MSI)-high tumors. Therefore, sufficient sampling of histological specimens is necessary in cases of unresectable pancreatic cancer (UR-PC). This multicenter study investigated the efficacy of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) using a Franseen needle for MSI evaluation in patients with UR-PC. Methods: A total of 89 patients with UR-PC who underwent endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) or EUS-FNB using 22-G needles at three hospitals in Japan (2018–2021) were enrolled. Fifty-six of these patients (FNB 23 and FNA 33) were followed up or evaluated for MSI. Patient characteristics, UR-PC data, and procedural outcomes were compared between patients who underwent EUS-FNB and those who underwent EUS-FNA. Results: No significant difference in terms of sufficient tissue acquisition for histology was observed between patients who underwent EUS-FNB and those who underwent EUS-FNA. MSI evaluation was possible significantly more with tissue samples obtained using EUS-FNB than with tissue samples obtained using EUS-FNA (82.6% [19/23] vs. 45.5% [15/33], respectively; p<0.01). In the multivariate analysis, EUS-FNB was the only significant factor influencing the possibility of MSI evaluation. Conclusions EUS-FNB using a Franseen needle is desirable for ensuring sufficient tissue acquisition for MSI evaluation.

OBJECTIVE: Programmed cell death-ligand 1 (PD-L1) is expressed in tumor cells and has been shown to predict clinical outcomes of several types of malignancies. The aim of this study was to investigate the effects of carbon-ion (C-ion) beam irradiation on PD-L1 expression in human uterine cervical adeno/adenosquamous carcinoma (UCAA) cells and clinical samples and to identify the prognostic factors for outcomes after C-ion radiotherapy (CIRT). METHODS: The effects of C-ion irradiation on PD-L1 expression in human UCAA and cervical squamous cell carcinoma cells were examined by flow cytometry. We examined PD-L1 expression in UCAA biopsy specimens from 33 patients before CIRT started (pre-CIRT) and after 12 Gy (relative biological effectiveness [RBE]) irradiation (post-12Gy-C) in 4 fractions of CIRT to investigate the correlation between PD-L1 status and clinical outcomes. RESULTS: The PD-L1 expression was upregulated by C-ion beam in a dose-dependent manner in HeLa and SiHa cells through phosphorylated Chk1. The overall frequencies of pre-CIRT and post-12Gy-C PD-L1 positivity were 45% (15/33) and 67% (22/33), respectively. The post-12Gy-C PD-L1 expression was significantly elevated compared to the pre-CIRT PD-L1 expression. There was no significant relationship between the pre-CIRT PD-L1 status and clinical outcomes, such as local control (LC), progression-free survival (PFS), and overall survival (OS). However, the post-12Gy-C PD-L1 expression had better correlation with PFS, but not with LC and OS. CONCLUSION CIRT can induce PD-L1 expression in UCAA and we propose that PD-L1 expression after starting CIRT may become as a predictive prognostic marker in CIRT for UCAA.