Effect of Bakumondo-to on cytochrome P450 activities in rat liver microsomes

AbstractBakumondo-to is a traditional herbal medicine. It has been widely used for the treatment of chronic airway diseases. Recently, it was reported that several herbal medicines affected cytochrome P450 (CYP). However, there is little information about the effects of Bakumondo-to on CYP activities. In this study, we evaluated the effects of Bakumondo-to on CYP activities in rat liver microsomes. Rats were orally treated twice a day with Bakumondo-to at doses of 2.0g/kg body weight/day for 4days. CYP activities were determined in liver microsomes isolated from treated rats. CYP1A2, CYP2C, and CYP3A activities were measured using their specific substrates [7-methoxyresorufin, 7-methoxy-4-(trifluoromethyl)-coumarin, and 7-benzyloxyquinoline, respectively]. Bakumondo-to decreased CYP1A2 activity by 42.5±7.8%, increased CYP2C activity by 158.0±29.6%, and decreased CYP3A activity to 81.5±7.8% of the control level. Activities were expressed as percentages of the control.Bakumondo-to induced CYP2C activity and decreased CYP1A2 activity; it may cause drug-herbal interactions. It is suggested that combinations of Bakumondo-to and drugs that are metabolized by CYP1A2 and CYP2C should be carefully used in clinical settings

限局性腎細胞癌における腫瘍浸潤性リンパ球と関連サイトカインの予後因子としての意義

Renal cell carcinoma (RCC) is an immunogenic tumor and pathological specimen generally contain large quantities of tumor-infiltrating lymphocytes (TILs). Numerous cell types and cytokines could affect the immune escape mechanism of tumor cells. The aim of the present study was to investigate the prognostic impact of TILs and the associated circulating cytokines on localized clear cell RCC following radical nephrectomy. A total of 87 patients who had undergone radical nephrectomy and were pathologically diagnosed with localized clear cell RCC were included. The present study evaluated the profile of TILs with immunohistochemical analysis of tumor specimens using a panel of antibodies [cluster of differentiation (CD)-4, CD8, CD80, CD86, CD276, and Forkhead box p3 (Foxp3)]. Counts of each TIL were compared with clinicopathological variables. Based on the results of immunohistochemical analyses, putative cytokines, including interleukin (IL)-6, IL-10, IL-17, interferon-γ, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β, were selected, and their levels in preoperative serum were measured by ELISA. The levels were compared with TIL counts in tumor specimens. High counts of the CD276+ and Foxp3+ TILs were identified as independent factors for poor prognosis for metastasis and local recurrence following radical nephrectomy (P=0.033 and 0.006, respectively). A high CD276+ TIL count was associated with preoperative serum levels of TNF-α and IFN-γ (P=0.027 and P=0.035, respectively), whereas a high count of Foxp3+ TILs was associated with preoperative serum levels of TGF-β (P=0.021). High levels of TNF-α and TGF-β were associated with recurrence-free survival (P=0.035 and P=0.031, respectively). Topical intra-tumoral immunoreaction and systemic immune status may be associated with patients with localized RCC. The topical induction of the CD276+ and Foxp3+ TILs was suggested to be associated with high levels of serum TNF-α and IFN-γ. Preoperative serum levels of TNF-α and TGF-β could be simple and non-invasive biomarkers for risk stratification before radical surgery.博士（医学）・甲第741号・令和2年3月16日Copyright © Spandidos Publications 2019. All rights reserved.Articles from Oncology Letters are provided here courtesy of Spandidos Publications

ジョウチョウカンマク ジョウミャク ケッセンショウ ノ イチレイ

We report a case of superior mesenteric vein thrombosis successfully saved by resection of enteral necrosis. A ６７ years-old man who admitted for abdominal pain was diagnosed with acute enterocolitis and treated. After two days, abdominal pain increased and abdominal CT revealed superior mesenteric vein thrombosis. He was referred to the department of surgery. We conducted emergency operation. During surgery, bloody ascites and the enteral necrosis about５０cm in length was confirmed. The necrotic ileum was resected and an end-to-end anastomosis was performed. Immediately after surgery, we started anticoagulation therapy. The patient recoverd well and was discharged on POD３２． In a slow pattern like this case, we should suspect superior mesenteric vein thrombosis and diagnose by abdominal CT

ダイチョウ ガン ニ タイスル 5 FU アイソボリン リョウホウ デ コウカ ガ ミトメラレタ 2レイ

We report 2 cases of rectal cancer responding to postoperative chemotherapy with 5-fluorouracil and isovorin. Case 1 : A 60 years-old woman underwent low-anterior resection for rectal cancer in 1994 and partial right lung resection for metastatic lung cancer in 1998. She underwent chemotherapy with 5-fluorouracil and isovorin for mediastinal lymph node metastasis and high score of serum CEA in 2000. After the chemotherapy, the lymph node shrank and serum CEA normalized. Case 2 : A 75 years-old woman underwent low-anterior resection and hysterectomy for rectal cancer with multiple lung metastasis in 2000. She underwent postoperative chemotherapy with 5-fluorouracil and isovorin for metastatic lung cancer. The lung tumor shrank and serum CEA decreased. Chemotherapy with 5-fluorouracil and isovorin seemed to be effective for advanced colon cancer. We should reconfirm the effectiveness and improve the directions for use

Assessing Versatile Machine Learning Models for Glioma Radiogenomic Studies across Hospitals

Radiogenomics use non-invasively obtained imaging data, such as magnetic resonance imaging (MRI), to predict critical biomarkers of patients. Developing an accurate machine learning (ML) technique for MRI requires data from hundreds of patients, which cannot be gathered from any single local hospital. Hence, a model universally applicable to multiple cohorts/hospitals is required. We applied various ML and image pre-processing procedures on a glioma dataset from The Cancer Image Archive (TCIA, n = 159). The models that showed a high level of accuracy in predicting glioblastoma or WHO Grade II and III glioma using the TCIA dataset, were then tested for the data from the National Cancer Center Hospital, Japan (NCC, n = 166) whether they could maintain similar levels of high accuracy. Results: we confirmed that our ML procedure achieved a level of accuracy (AUROC = 0.904) comparable to that shown previously by the deep-learning methods using TCIA. However, when we directly applied the model to the NCC dataset, its AUROC dropped to 0.383. Introduction of standardization and dimension reduction procedures before classification without re-training improved the prediction accuracy obtained using NCC (0.804) without a loss in prediction accuracy for the TCIA dataset. Furthermore, we confirmed the same tendency in a model for IDH1/2 mutation prediction with standardization and application of dimension reduction that was also applicable to multiple hospitals. Our results demonstrated that overfitting may occur when an ML method providing the highest accuracy in a small training dataset is used for different heterogeneous data sets, and suggested a promising process for developing an ML method applicable to multiple cohort

尿路上皮癌微小環境内におけるDisabled Homolog 2 (DAB2) は腫瘍細胞上皮間葉転換を介して遊走能・浸潤能を高める

Disabled homolog-2 (DAB2) has been reported to be a tumor suppressor gene. However, a number of contrary studies suggested that DAB2 promotes tumor invasion in urothelial carcinoma of the bladder (UCB). Here, we investigated the clinical role and biological function of DAB2 in human UCB. Immunohistochemical staining analysis for DAB2 was carried out on UCB tissue specimens. DAB2 expression levels were compared with clinicopathological factors. DAB2 was knocked-down by small interfering RNA (siRNA) transfection, and then its effects on cell proliferation, invasion, and migration, and changes to epithelial-mesenchymal transition (EMT)-related proteins were evaluated. In our in vivo assays, tumor-bearing athymic nude mice subcutaneously inoculated with human UCB cells (MGH-U-3 or UM-UC-3) were treated by DAB2-targeting siRNA. Higher expression of DAB2 was associated with higher clinical T category, high tumor grade, and poor oncological outcome. The knock-down of DAB2 decreased both invasion and migration ability and expression of EMT-related proteins. Significant inhibitory effects on tumor growth and invasion were observed in xenograft tumors of UM-UC-3 treated by DAB2-targeting siRNA. Our findings suggested that DAB2 expression was associated with poor prognosis through increased oncogenic properties including tumor proliferation, migration, invasion, and enhancement of EMT in human UCB.博士（医学）・甲第768号・令和3年3月15日© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

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

The Failure of Agricultural Policy Reform in Neoliberal Japan: The 2007 Multi-Product Management Stabilization Plan

PhD University of Hawaii at Manoa 2014Includes bibliographical references (leaves 246–259).This dissertation is a geography of a failed attempt to change state-society relations in Japanese agriculture, examining a policy that tried to require family farms to become corporate entities. The study traces the rationale for state neoliberalism in Japanese agriculture, the particular reform aimed at the practices of rural communities, and the fate of that policy. Neoliberalism is a range of economic policies favoring free markets, de-coupling from state support, and privatization. Japanese agriculture became a target of neoliberal thinkers because sub-sectors rely on state protections and farm scale and land use are thought inefficient. Anticipating that Japanese agriculture would face wider import streams and lower rice subsidies, neoliberal politicians adopted a 2007 national measure known as the Multi-Product Management Stabilization Plan, Hinmoku Ōdanteki Kei'ei Antei Taisaku. This "Multi-Product Plan" was neoliberal in that it declared only core farmers and Cooperative Farming above a certain size would be eligible for future subsidies, and tried to develop these bodies into profitable operations. The plan required Cooperative Farming land pools to rationalize and incorporate the management of small rice farmers. Small producers could not otherwise remain eligible for subsidies. I investigated how the Ministry of Agriculture, Fisheries, and Forestry (MAFF) rolled out the Multi-Product Plan, how farmers tried to consolidate their management under the Multi-Product Plan; how farmers struggled with the plan in practice; and how politicians, agents, and researchers evaluated the plan's fit with the practices of farmers. Methods included interviews with staff in government agencies from national to local scales, and with leaders of rural communities. The Tōhoku Region was the site of the case study owing to its high dependency on rice farming. I interviewed staff of governments and related agencies across the six prefectures of that region. To understand the fit of the plan with local production and farmers' evaluation of the Multi-Product Plan, I chose Daisen City in the Senboku Region, Akita Prefecture, as a focus. My research found that the Multi-Product Plan could not succeed locally, continue politically, nor restructure Japanese agriculture. Farmers derailed Japan's developmental neoliberal policy in this instance