Adipose tissue : Critical contributor to the development of prostate cancer

The prostate is surrounded by periprostatic adipose tissue. Although adipose tissue was thought to play limited physiological roles, it has recently been recognized as an active endocrine organ, secreting growth factors and adipokines. Epidemiologically, obesity is associated with prostate cancer progression. A major mechanism to explain the link between obesity and cancer includes the insulin and insulin-like growth factor (IGF)-1 axis, sex steroids, and adipokines. When prostate cancer cells invade periprostatic adipose tissue, adipose tissue contributes to create the tumor microenvironment, mainly via adipokine secretion. Furthermore, direct crosstalk between adipocytes and cancer cells can exist.We showed that fatty acid-binding protein 4 (FABP4) released from adipocytes was taken up into prostate cancer cells and may act as a carrier of an energy source for the invasion. Bone is an adipocyte-rich organ and is the common metastatic site of prostate cancer. In the microenvironment of bone metastases, tumor cells, osteoblasts, osteoclasts, adipocytes, and other stromal cells are interacting with one another and organizing a complex system. Thus, growing evidence implicates adipose tissue as a critical contributor to the development of prostate cancer. A deeper understanding of the mechanisms leads to more effective therapeutic strategies for prostate cancer

Therapeutic regimen of l-arginine for MELAS: 9-year, prospective, multicenter, clinical research

ObjectiveTo examine the efficacy and safety of the therapeutic regimen using oral and intravenous l-arginine for pediatric and adult patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).MethodsIn the presence and absence of an ictus of stroke-like episodes within 6 h prior to efficacy assessment, we correspondingly conducted the systematic administration of oral and intravenous l-arginine to 15 and 10 patients with MELAS in two, 2-year, prospective, multicenter clinical trials at 10 medical institutions in Japan. Subsequently, patients were followed up for 7 years. The primary endpoint in the clinical trial of oral l-arginine was the MELAS scale, while that for intravenous l-arginine was the improvement rates of headache and nausea/vomiting at 2 h after completion of the initial intravenous administration. The relationships between the ictuses of stroke-like episodes and plasma arginine concentrations were examined.ResultsOral l-arginine extended the interictal phase (p = 0.0625) and decreased the incidence and severity of ictuses. Intravenous l-arginine improved the rates of four major symptoms—headache, nausea/vomiting, impaired consciousness, and visual disturbance. The maximal plasma arginine concentration was 167 μmol/L when an ictus developed. Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. No treatment-related adverse events occurred, and the formulations of l-arginine were well tolerated.ConclusionsThe systematic administration of oral and intravenous l-arginine may be therapeutically beneficial and clinically useful for patients with MELAS

子宮内膜症性腸閉塞に対する経肛門的イレウスチューブの有用性

One of the causative diseases of intestinal obstruction in young women is bowel endometriosis. During the course of ectopic endometriosis, it is estimated that about １０％ of patients develop bowel endometriosis. The first step in treatment is drug therapy. In cases of bowel endometriosis of the colon or rectum leading to intestinal obstruction, laparotomy is often required. A ４７-year-old woman with a history of endometriosis was undergoing drug therapy. She developed abdominal pain and nausea, and was diagnosed with septic shock and fecal ileus. A transanal drainage tube was inserted for decompression. The patient’s general condition improved, and a laparoscopic low anterior resection was performed on the ２３rd day. The patient was discharged on the １０th postoperative day without any postoperative problems. This case suggests that even in the case of septic shock caused by rectal stricture due to intestinal endometriosis, initial treatment with transanal decompression may stabilize the general condition, and may be superior in cosmetic change

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

信州大学博士（医学）・学位論文・平成25年3月31日授与（甲第942号）・楊 磊Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after percutaneous coronary intervention. Calcitonin gene-related peptide (CGRP) is produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene. Originally identified as a strongly vasodilatory neuropeptide, CGRP is now known to be a pleiotropic peptide widely distributed in various organs and tissues. Our aim was to investigate the possibility that CGRP acts as an endogenous vasoprotective molecule. We compared the effect of CGRP deficiency on neointimal formation after wire-induced vascular injury in wild-type and CGRP knockout (CGRP-/-) mice. We found that neointimal formation after vascular injury was markedly enhanced in CGRP-/- mice, which also showed a higher degree of oxidative stress, as indicated by reduced expression of nitric oxide synthase, increased expression of p47phox, and elevated levels of 4HNE, as well as greater infiltration of macrophages. In addition, CGRP-deficiency led to increased vascular smooth muscle cell (VSMC) proliferation within the neointima. By contrast, bone marrow-derived cells had little or no effect on neointimal formation in CGRP-/- mice. In vitro analysis showed that CGRP-treatment suppressed VSMC proliferation, migration, and ERK1/2 activity. These results clearly demonstrate that endogenous CGRP suppresses the oxidative stress and VSMC proliferation induced by vascular injury. As a vasoprotective molecule, CGRP could be an important therapeutic target in cardiovascular disease. (C) 2013 Elsevier Ltd. All rights reserved.ArticleJOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY. 59(0):55-66 (2013)journal articl

ショクギョウ ト パーソナリティ ケンキュウ ノ シュヨウ ガイネン ト コウゴ サヨウ コウカ

本稿は、Melvin L. Kohn とCarmi Schooler を中心とする職業とパーソナリティ研究を紹介するものである。職業とパーソナリティ研究とは、アメリカにおける長期的パネル調査と、アメリカ、ポーランド、日本、ウクライナにおける国際比較務査による一連の研究を指している。本稿では、アメリカの第ニ波調査まで取り上げる。まず、初期の代表的著作である、Class and Conformity(Kohn[1969]1977)から、職業とパーソナリティ研究の生まれた経緯を概説する。この著作において、Kohn は、階級・階層が職業の諸条件を決定し、その職業の諸条件が人びとのパーソナリティに影響を及ぼす、と主張した。これを本稿ではClass and Conformity仮説と呼び、職業とパーソナリティ研究の主要概念と基本的な分析視座を提示したものと位置づけた。この仮説は、Work and Personality (Kohn and Schooler 1983)において継続され、発展する。ここで、職業とパーソナリティの因果関係が、一方向から双方向へと捉えなおされたのである。つまり、職業とパーソナリティの間には交互作用効果が存在する。これを本稿では、Work and Personality仮説と呼んだ。この仮説は女性、余暇、家事といった領域へと拡張されていき、彼らのその後の研究における仮説の一般化という流れを方向づけた。This paper reviews studies of work and personality conducted by Melvin L. Kohn, Carmi Schooler and their colleagues since the late 1950s. Their studies are based on the long-term panel surveys in America and cross-national surveys comparing America, Poland, Japan and Ukraine. In this paper, we focus on the main research literature of the first and the second wave panel studies in America. First, we examine Class and Conformity (Kohn [1969]1977). In this book, Kohn constructed the fundamental concepts and ideas of Work and Personality Studies. The main conclusion of this book is that social stratification position affects an individual' s conditions of work, and these conditions of work in tum affect their personality. We call this causal relationship the “Class and Conformity thesis". The book provides the basic framework for subsequent studies. In Work and Personality (Kohn and Schooler 1983), Kohn and Schooler develop this basic framework further. In this book, they argued that there are reciprocal effects between work and personality. Reciprocal effects mean that work both affects and is affected by personality. We call this relationship the “Work and Personality thesis. They also try to expand the subjects and arenas explained by this thesis. First, they explore whether the thesis is applicable to not only men but also women. Second, they try to apply the thesis to the relationship between personality and leisure time activities or household affairs. These analyses of women, leisure time activities, and household affairs lead to their subsequent studies

2型糖尿病成人男性患者の病気の体験 : ライフヒストリー法を用いたナラティブアプローチ

我々は、生活習慣病としての糖尿病患者の病気の体験を明らかにするためには、その人の生活に焦点をあてること、つまりその人の糖尿病に関連した過去から現在までのフィールドを、その人の意味づけの中で、その人自身の語り(ナラティブ)から見ていくことが重要であると考えた。そこで、本研究は、個人に焦点をあて、生活、つまり身の回りの具体的な関係を対象とし、個人が自らの言葉で語ること(ナラティブ)を大事にするライフヒストリー法を用いて、2型糖尿病成人男性患者がどのように病気を体験しているのかを明らかにすることを目的とした。研究方法は、ライフヒストリー法を用いた。データ分析は、インタビューによって得られた対象者の語り(ナラティブ)を聞き手である研究者がライフヒストリーヘと構成し、語り手によって自覚化された病気の体験を明らかにしていった。対象者は、研究参加への同意が得られた4人の糖尿病成人男性患者であった。 2型糖尿病成人男性患者は、ライフヒストリー法を用いたナラティブアプローチによって、病気の体験を自覚化していった。ナラティブアプローチによって自覚化された病気の体験は、「解放された身体」「免罪された身体」「大事にしたい身体」「治る(症状が消えた)身体」であった。「解放された身体」を自覚化していったAさんは、自分の能力を糖尿病(親の持っている病気)を含めた身体の能力として解釈していた。そのAさんはライフヒストリーの語りの中で、の体験を語り、自分の身体へ関心を向け、身体へ気遣いを向けられるようになっていった。「免罪された身体」を自覚化していったBさんは、病気になったら会社も人生も終わりになり、何もすることがなくなると解釈していた。そのBさんはライフヒストリーの語りの中で、生活を自覚してこなかったの体験を語り、自分を許し、地元の名士の言葉で自分が許されたことで自分の身体を気遣う気持ちを表していった。一方、「大事にしたい身作土を自覚化していったCさんは、が、糖尿病によってとなり自分が恥ずかしいと解釈していた。ライフヒストリーの語りの中で、の体験を語り、今からは大事にしたいという自分を芽生えさせていった。さらに、「活る(症状が消える)身体」を自覚化していったDさんは、という生活への対処を身につけており、糖尿病の療養法を簡単に活してくれるものと解釈していた。Dさんはライフヒストリーの語りの中で、体験を語り、自分の病気、身体へ関心を向け始めていった。これらのことから、人が生活習慣病としての糖尿病の療養に取り組んでいくためには、「習慣としての身体」を意識にあげていく必要があることが示唆された。We considered it important to direct particular attention to the life history of patients with diabetes mellitus, which is a lifestyle-related disease, and to clarify the disease experience of patients by analyzing the course of a patient\u27s life from the past to the present as it is narrated by the patient according to his/her interpretation. In this study, therefore, we focused on individual patients and evaluated their concrete relationships with people around them by the life history method, based on narratives of the patients them-selves to clarify their disease experiences. The subjects were 4 adult males with type II diabetes mellitus who consented to the study. Their narratives, recorded during interviews, were reconstituted into life histories by the researcher who interviewed them, and the disease experiences perceived by the narrators were presented. The subjects became conscious of their disease experiences through the narrative approach using the life history method. The disease experiences made conscious by the narrative approach were "the body being set free", "the body being acquitted", "the body that the patient wants to take good care of", and "the body being cured (relieved from symptoms)". Mr. A, who became conscious of his "body being set free", interpreted his abilities as those of his body including diabetes mellitus (disease inherited from his parents). He described an experience in his narration of his life history of having felt his body becoming light as if a lead plate had been detached from it. He then directed his attention to his body, and he became able to take good care of it. Mr. B, who became aware of his "body being acquitted", considered that both his company and his personal life had ended as he became ill, and that he would have nothing to do. He talked about "bad me" not having paid due attention to his life, forgave himself, and began to express his will to pay more attention to his body, after he felt forgiven by the words of a local prominent person. Mr. C, who became conscious of "the body that he wanted to take good care of", had thought that diabetes made "his body that he had created" "a less attractive body that had lost bone", and he was ashamed of himself. He talked about his experience of "losing the attractiveness (bone) of his body" in his narration of his life history and began to feel that he should take better care of his body. Mr. D, who became conscious of "the body being cured (relieved from symptoms)", had acquired a lifestyle of "taking things for granted" and expected that his disease would be cured easily. He described his experience of "cure of his disease (disappearance of symptoms)" in his narration of his life history, and began to have more interest in his disease and his body. These observations suggest that patients must become conscious of "the body as a result of a lifestyle" before they can seriously face treatment for diabetes mellitus as a lifestyle-related disease

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

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection