Aldo–Keto Reductase 1B10 and Its Role in Proliferation Capacity of Drug-Resistant Cancers

The human aldo–keto reductase AKR1B10, originally identified as an aldose reductase-like protein and human small intestine aldose reductase, is a cytosolic NADPH-dependent reductase that metabolizes a variety of endogenous compounds, such as aromatic and aliphatic aldehydes and dicarbonyl compounds, and some drug ketones. The enzyme is highly expressed in solid tumors of several tissues including lung and liver, and as such has received considerable interest as a relevant biomarker for the development of those tumors. In addition, AKR1B10 has been recently reported to be significantly up-regulated in some cancer cell lines (medulloblastoma D341 and colon cancer HT29) acquiring resistance toward chemotherapeutic agents (cyclophosphamide and mitomycin c), suggesting the validity of the enzyme as a chemoresistance marker. Although the detailed information on the AKR1B10-mediated mechanisms leading to the drug resistance process is not well understood so far, the enzyme has been proposed to be involved in functional regulations of cell proliferation and metabolism of drugs and endogenous lipids during the development of chemoresistance. This article reviews the current literature focusing mainly on expression profile and roles of AKR1B10 in the drug resistance of cancer cells. Recent developments of AKR1B10 inhibitors and their usefulness in restoring sensitivity to anticancer drugs are also reviewed

Low-dose Warfarin Functions as an Immunomodulator to Prevent Cyclophosphamide-induced NOD Diabetes

Warfarin has been used as an anticoagulant for a long time. Recently, the pleiotropic effect of warfarin has been investigated. As low-dose warfarin has been reported to have anti-inflammatory effect through suppression of IL-6 secretion and inhibit the immune-associated signal between Tyro3 and its ligand, Gas6, the effect of low-dose warfarin on autoimmune diabetes in NOD mice was examined. To investigate the anti-inflammatory effect of warfarin, IL-6 secretion by splenocytes was examined in the presence of various concentrations of warfarin. Low concentration of warfarin inhibited IL-6 secretion. mRNA expression of Rse, one of the Tyro3 receptor family members, and Gas6 were analyzed in NOD mice. It was detected in islets, splenocytes and bone-marrow derived dendritic cells. 0.25 mg/l or 0.50 mg/l of warfarin was orally administered to NOD mice as a cyclophosphamide-induced diabetes model. Oral administration of warfarin at much lower doses than those clinically used as an anticoagulant significantly reduced the degree of insulitis and diabetes incidence in this model. We previously demonstrated that anti-FasL Ab-treatment led to complete prevention of autoimmune diabetes in NOD mice. As Fas/FasL signaling is reported to be essential for cyclophosphamide-induced diabetes model, we extracted RNA from lymphocytes of the inguinal lymph nodes of anti-FasL Ab-treated NOD mice and performed real-time PCR to determine expression of Rse gene. Interestingly, the expression of Rse gene related to the blockade of Fas/FasL signaling was reduced to less than half the level of untreated mice. In conclusion, low-dose warfarin is a potential immunomodulator which can prevent autoimmune diabetes. Type 1 diabetes is a chronic autoimmune disease caused by autoreactive T cells promoting the specific destruction of insulin-producing β cells of the pancreatic islets (1,6). Nonobese diabetic (NOD) mouse is an animal model of human autoimmune diabetes (19). In the NOD mouse, diabetes develops as the result of a chronic inflammation that starts with leukocytic infiltration of islets from 3-5 weeks of age and gradually exacerbates until hyperglycemia develops after 16 weeks of age in a high percentage of female mice. Warfarin has been widely used for a long time as an oral anticoagulant agent. In addition, Kater et al. reported the pleiotropic effect of low-dose warfarin related with inflammation, demonstrating that low-dose warfarin inhibited inflammatory signal transduction through suppression of TNF-α induced IL-6 secretion from murine macrophages (12)

Seven-plus hours of daily sedentary time and the subsequent risk of breast cancer : Japan Multi-Institutional Collaborative Cohort Study

This study aimed to investigate the association between daily sedentary time and the risk of breast cancer (BC) in a large Japanese population. The participants were 36,023 women aged 35–69 years from the Japan Multi-Institutional Collaborative Cohort Study. Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for BC incidence in relation to time spent sedentarily (categorical variables: <7 and ≥7 hours/day [h/d]). Additionally, the associations of BC incidence to the joint effect of sedentary time with each component of physical activity, such as leisure-time metabolic equivalents (METs), frequency of leisure-time physical activity, and daily walking time, were examined. During 315,189 person-years of follow-up, 554 incident cases of BC were identified. When compared to participants who spent <7 h/d sedentary, those who spent ≥7 h/d sedentary have a significantly higher risk of BC (HR, 1.36; 95% CI, 1.07–1.71). The corresponding HRs among participants who spent ≥7 h/d sedentary with more physical activity, such as ≥1 h/d for leisure-time METs, ≥3 days/week of leisure-time physical activity, and ≥1 h/d of daily walking were 1.58 (95% CI, 1.11–2.25), 1.77 (95% CI, 1.20–2.61), and 1.42 (95% CI, 1.10–1.83), respectively, compared with those who spent <7 h/d sedentary. This study found that spending ≥7 h/d of sedentary time is associated with the risk of BC. Neither leisure-time physical activity nor walking had a BC-preventive effect in those with ≥7 h/d of sedentary time

ICU治療肺炎の原因微生物

ICU 治療肺炎の原因微生物を明らかにすることを目的とした．ICU で治療が行われた市中肺炎43例を対象とし，これら症例の原因微生物をretrospective に検討した．その結果，29例（67％）で原因微生物が検出され，その内訳は，Streptococcus pneumoniae 9例，Methicillin-sensitive Staphylococcus aureus（ MSSA） 8例，Legionella pneumophila 4例，Haemophilus influenzae ３例，Klebsiella pneumoniae 3例，Pseudomonas aeruginosa 2例であった．The purpose was to clarify the causative organisms of Intensive Care Unit treatment pneumonia. Forty-three patients with severe community-acquire pneumonia who were treated in ICU and the causative organisms of these patients were retrospectively examined. As a result, the causative organisms were detected in 29 patients (67%) including Streptococcus pneumoniae in 9 patients, Methicillin-sensitive Staphylococcus aureus (MSSA) in 8 patients, Legionella pneumophila in 4 patients, Haemophilus influenzae in 3 patients, Klebsiella pneumoniae in 3 patients, Pseudomonas aeruginosa in 2 patients

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

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

コウダイレンケイ ニ ヨル キョウイク コウリュウ ネットワーク ノ コウチク : コミュニケーション キョウイク ケンキュウカイ ノ カツドウ ト コミュニケーションリテラシー

高大連携校より本学への入学が決定した生徒を対象とした単位認定科目「コミュニケーションリテラシー」を開講した。同科目の内容やスケジュールは、平成19 年度よりほぼ月に一度のペースで高大連携協定校教員と本学教職員で構成する「コミュニケーション教育研究会」で調査研究・見学・参観・討議などを重ねて決定されたものである。この研究会の中ではまた、ブレインストーミングにより、経済産業省の「社会人基礎能力」を基本とした「職業を持った社会人に必要とされる能力要素」の洗い出しを行ない、これら要素の必要性や獲得度のアンケート調査を実施した。対象は高大連携校と全国の高校である。その結果、職業をもった社会人にもっとも必要とされる基本的な基礎能力は、「コミュニケーション能力」と「一般常識」であること、さらには「課題発見能力や企画・提案能力」や「表現力やプレゼンテーション能力」が不十分であるととらえられていることがわかった。こうした問題意識を踏まえて「コミュニケーションリテラシー」の実施内容を組み立てた。本年度の「コミュニケーションリテラシー」受講生は110 名となった。この効果を検証することは容易ではないが、受講生に対しアンケート調査などを行った結果に関しても報告する。Novel coordination program, namely, "Communication Literacy", consisting of 15 lesson classes, was developed and held for secondary school third grade students. This class was developed and implemented in a project set up with members from secondary school teachers and Shohoku College teachers and staff. Survey on basic vocational abilities necessary for the graduates was made by sending questionnaires to secondary school teachers. Questionnaires were made to students participated in the program to clarify the effect of the program

コウダイ レンケイ ニ ヨル セツゾクキョウイク プログラム カイハツ ノ ココロミ

高大連携により効率的な接続教育プログラムを開発するため,高校向けアンケートを実施した。職業に就いた際に必要とされるキャリア基礎能力として本学で過去実施したアンケート結果を基にした10 要素,ならびに経済産業省の「社会人基礎力」12 要素の必要性と達成度を設問とした。その結果,社会人にもっとも必要とされるキャリア基礎能力は「コミュニケーション能力」であること,また,高校教科「情報」によりPC 基礎操作能力は十分獲得されていること,がわかった。この結果を踏まえ,高大連携プログラムの一環として高校-大学教員によるコミュニケーション教育研究会を開催し,全12 講からなる接続教育プログラム「コミュニケーションリテラシー」を開講した。Enquiries were made to upper secondary school teachers on basic vocational abilities necessary for thegraduates. Since "information literacy" was introduced recently as compulsory subject in secondary schools, itsrelation with elements necessary for an ordinary person who wishes to work in a company was investigated. Basedon the results, a project was set up with members from secondary school teachers and Shohoku College teachersand library staff. As a result, a novel coordination program, namely, "communication literacy", consisting of 12lessons, was held for secondary school third grade students