ヒト肝細胞癌においてherpesvirus entry mediatorの発現がもたらす影響

BACKGROUND: Herpes virus entry mediator (HVEM), also known as tumour necrosis factor receptor (TNFR) superfamily 14, regulates a variety of physiological and pathological responses in both innate and acquired immunity. Although HVEM is also suggested to be a critical regulator in tumours, actual roles in human cancer are largely unknown. This study aimed to clarify clinical importance of HVEM in human hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We studied HVEM expression in 150 HCC patients to explore its clinical relevance, and we examined tumour infiltrating T cells and local immune status of them. RESULTS: HVEM was expressed in HCC cells, while no or only limited expression was observed in normal tissues in the liver. Tumour HVEM expression was significantly correlated with age, serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) level, vascular invasion and tumour node metastasis (TNM) stage. Furthermore, tumour HVEM expression significantly correlated with postoperative recurrence and survival. Importantly, multivariate analysis indicated that the HVEM status had an independent prognostic value. Furthermore, HVEM status was inversely correlated with tumour-infiltrating CD4(+), CD8(+) and CD45RO(+) lymphocytes. In addition, it was also associated with reduced expression of perforin, granzyme B and interferon-γ (IFN-γ). Taken together, tumour-expressing HVEM plays a functionally important role in HCC. CONCLUSION: Tumour-expressing HVEM plays a critical role in human HCC, possibly through regulating immune evasion. Therefore, targeting HVEM may be a novel promising therapeutic strategy for HCC.博士（医学）・乙第1359号・平成27年5月28日Copyright © 2014 Elsevier Ltd

下部直腸癌における側方リンパ節転移に関して、造影MRI で描出される中直腸動脈の転移予測因子に関する検討

Purpose: Lateral lymph node (LLN) metastasis is one of the leading causes of local recurrence in patients with lower rectal cancer. Unfortunately, no diagnostic biomarkers are currently available that can predict LLN metastasis preoperatively. Accordingly, we investigated the relationship between the middle rectal artery (MRA) identified by contrast-enhanced magnetic resonance imaging (ceMRI) and LLN metastases. Methods: Data from 102 patients with lower rectal cancer who underwent surgery, and were evaluated by preoperative ceMRI, between 2008 and 2016 were reviewed retrospectively. Two expert radiologists evaluated the MRA findings. The diagnostic performance of MRA for LLN metastasis was evaluated by a multivariate analysis with conventional clinicopathological factors. Results: The MRA was detected in 67 patients (65.7%), including 32 (31.4%) with bilateral MRA and 35 (34.3%) with unilateral MRA. The tumor size, presence of the MRA, and clinical LLN status were significantly correlated with LLN metastasis. A multivariate analysis demonstrated that the presence of MRA (P = 0.045) and clinical LLN status (P = 0.001) were independent predictive factors for LLN metastasis. Furthermore, the sensitivity and negative predictive value of MRA for LLN metastasis were 95% and 97.1%, respectively. Conclusion: We successfully demonstrated that MRAs could be clearly detected by ceMRI, and the presence of MRA robustly predicted LLN metastasis in patients with lower rectal cancer, highlighting its clinical significance in the selection of more appropriate treatment strategies. Trial registration: Trial registration number: retrospectively registered 2126 Trial registration date of registration: August 23, 2019.博士（医学）・乙第1512号・令和3年12月21日© 2021. The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/

ヒト大腸癌におけるHVEM発現は腫瘍の進行と予後に影響する

Background: Herpesvirus entry mediator (HVEM) has been recently suggested to play certain roles in cancer biology. We examined HVEM expression in human colorectal cancer (CRC) to reveal its clinical importance. Materials and Methods: Immunohistochemical staining was carried-out in normal epithelium, benign and malignant lesions. Results: While intense HVEM expression was not observed in normal epithelium and hyperplastic polyps, 24% of adenoma and more than half of CRCs had high HVEM expression. In 234 CRCs, HVEM expression was significantly associated with tumor status and pathological stage. Patients with high HVEM expression had a significantly poorer prognosis than those with low expression. Importantly, HVEM status had an independent prognostic value in CRC. Furthermore, HVEM status was inversely corrected with the presence of tumor-infiltrating T-cells. Conclusion: HVEM may play a critical role in tumor progression and immune evasion, and may also be a novel prognostic marker and potential therapeutic target in human CRC.博士（医学）・乙第1363号・平成27年7月31日発行元の規定により、本文の登録不可。本文は以下のURLを参照 "http://ar.iiarjournals.org/content/35/3/1361.abstract"　（※全文閲覧は学内限定

Supplementation With Whey Peptide Rich in β-Lactolin Improves Cognitive Performance in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Study

Epidemiological reports showed that consumptions of fermented dairy products are beneficial for cognitive decline in elderly. Our previous preclinical studies have demonstrated that intakes of whey peptide rich in the β-lactolin [β-lactopeptide of glycine-thereonine-tryptophan-tyrosine (GTWY)] improve memory and attention by regulating monoamine system, and clinical study using neuropsychological test suggested that consumptions with GTWY-rich whey peptide enhance cognitive performance associated with the frontal cortex activity. However, corresponding interventional studies in humans are limited. Objectives: to evaluate the effects of the whey peptide on cognitive functions in healthy older adults using a randomized, double-blinded, placebo-controlled trial design. 114 healthy subjects aged 50–75 were supplemented with the whey peptide or placebo for 12 weeks, and changes in cognitive function were assessed using neuropsychological tests at weeks 0, 6, and 12 of the intervention. Neuropsychological tests included assessments for memory functions (subtests from Wechsler memory scale-revised, standard verbal paired-associate learning test, and recognition memory test for faces), assessments for attention (cancelation and detection tests), and assessments for general cognitive functions (repeatable battery for assessments of neuropsychological status). Cerebral blood flow was also assessed using near-infrared spectroscopy (NIRS) after 6 weeks of intervention. This study was registered on the 19 November, 2017 in the database of the University Hospital Medical Information Network (UMIN) prior to enrollment of subjects (Registration No. UMIN000030461: https://www.umin.ac.jp/ctr/index-j.htm). In the whey peptide group, visual paired-associates I and visual cancelation tests were significantly improved compared with those in the placebo group at weeks 6 and 12 of the intervention, respectively. Visuospatial and constructional scores of the repeatable battery for assessments of neuropsychological status and standard verbal paired-associate learning tests (S-PA) also tended to be improved by the intervention at week 12. Daily intakes of GTWY-rich whey peptide show beneficial effects on cognitive performance, especially associative learning memory and control of attention, in healthy older adults and might prevent age-related cognitive declines

ヒロウ コンパイ ニ イタル シンチョウ タンシュク サイクル ウンドウ ガ カタイ サントウキン ノ シュウシュク トクセイ オヨビ ソンショウ シヒョウ ニ オヨボス エイキョウ

The repeated heel-raiseis a typical stretch-shortening cyc1e (SSC) exercise. The exercise is not only performed in resistance training but also used for evaluating muscular strength in c1inical settings. The present study was undertaken to investigate the effect of repeated heel-raise exercise to a volitional exhaustion on contractile properties of the triceps surae muscle and parameters reflecting muscle injury. Five Healthy university students with no orthopedic disorders served as subjects. Each subject performed two exercises. ln SSC condition，the subjects repeated the SSC exercise every 2 seconds to volitional exhaustion. ln the IS0 condition，they repeated the same number of an isometric exercise as that of the SSC exercise. In the SSC condition，the subjects exhausted after repeating the exercise 28.6 times. At exhaustion，maximal torque developing capacity decreased significantly and the decrease was accompanied by a tendency of a lower median power frequency of the EMG signals. A significantly higher lactate concenlration was also observed. On the other hand，the ISO exercise induced no significant changes in these parameters. In the SSC condition，the decreased maximal torque developing capacity at exhaustion remained one hour and even one day following the exhausting exercise. The circumference of the lower extremity became larger significantly at exhaustion as compared with the pre-exercise values and remained higher one hour and one day after the exercise. The pressure threshold for pain in the medial head of the gastrocnemius muscle and the muscle-tendon junction of the triceps surae muscle became significantly lower compared with pre-exercise value one hour or one day following the exercise. Muscle pain evaluated using visual analog scale f1uctuated and the higher value was observed at exhaustion and one day after SSC exercise. ln the ISO condition，no significant changes in these parameters were observed. The results of the present study indicated that the SSC exercise had more profound effects on contractile properties， myo-electrical signals and injury-related parameters than the ISO exercise. Furthermore, the results suggest that，even in a relatively small number of repetitions，repeated heel-raise, at ypical SSC exercise，induces as light muscle injury

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target