Nara Medical University Hospital
Global Institutional repository of Nara Medical UniversityNot a member yet
3071 research outputs found
Sort by
リポポリサッカライドの外因性投与はコリン欠乏 L-アミノ酸置換食誘発脂肪性肝炎モデルマウスにおいて肝線維化を促進する
Get PDFVarious rodent models have been proposed for basic research; however, the pathogenesis of human nonalcoholic steatohepatitis (NASH) is difficult to closely mimic. Lipopolysaccharide (LPS) has been reported to play a pivotal role in fibrosis development during NASH progression via activation of toll-like receptor 4 (TLR4) signaling. This study aimed to clarify the impact of low-dose LPS challenge on NASH pathological progression and to establish a novel murine NASH model. C57BL/6J mice were fed a choline-deficient l-amino-acid-defined (CDAA) diet to induce NASH, and low-dose LPS (0.5 mg/kg) was intraperitoneally injected thrice a week. CDAA-fed mice showed hepatic CD14 overexpression, and low-dose LPS challenge enhanced TLR4/NF-κB signaling activation in the liver of CDAA-fed mice. LPS challenge potentiated CDAA-diet-mediated insulin resistance, hepatic steatosis with upregulated lipogenic genes, and F4/80-positive macrophage infiltration with increased proinflammatory cytokines. It is noteworthy that LPS administration extensively boosted pericellular fibrosis with the activation of hepatic stellate cells in CDAA-fed mice. Exogenous LPS administration exacerbated pericellular fibrosis in CDAA-mediated steatohepatitis in mice. These findings suggest a key role for LPS/TLR4 signaling in NASH progression, and the authors therefore propose this as a suitable model to mimic human NASH.博士（医学）・甲第738号・令和2年3月16日© 2019 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/)
フォン・ヴィレブランド因子のA1 ドメインに対する新規アプタマー (TAGX-0004) はARC1779よりも強く、Caplacizumabと同等に血栓形成を阻害する
No full textvon Willebrand factor (VWF) is a blood glycoprotein that plays an important role in platelet thrombus formation through interaction between its A1 domain and platelet glycoprotein Ib. ARC1779, an aptamer to the VWF A1 domain, was evaluated in a clinical trial for acquired thrombotic thrombocytopenic purpura (aTTP). Subsequently, caplacizumab, an anti-VWF A1 domain nanobody, was approved for aTTP in Europe and the United States. We recently developed a novel DNA aptamer, TAGX-0004, to the VWF A1 domain; it contains an artificial base and demonstrates high affinity for VWF. To compare the effects of these three agents on VWF A1, their ability to inhibit ristocetin- or botrocetin-induced platelet aggregation under static conditions was analyzed, and the inhibition of thrombus formation under high shear stress was investigated in a microchip flow chamber system. In both assays, TAGX-0004 showed stronger inhibition than ARC1779, and had comparable inhibitory effects to caplacizumab. The binding sites of TAGX-0004 and ARC1779 were analyzed with surface plasmon resonance performed using alanine scanning mutagenesis of the VWF A1 domain. An electrophoretic mobility shift assay showed that R1395 and R1399 in the A1 domain bound to both aptamers. R1287, K1362, and R1392 contributed to ARC1779 binding, and F1366 was essential for TAGX-0004 binding. Surface plasmon resonance analysis of the binding sites of caplacizumab identified five amino acids in the VWF A1 domain (K1362, R1392, R1395, R1399, and K1406). These results suggested that TAGX-0004 possessed better pharmacological properties than caplacizumab in vitro and might be similarly promising for aTTP treatment.博士（医学）・甲第739号・令和2年3月16日Copyright © 2020 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter nal use. Sharing published material for non-commercial pur poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com mercial purposes is not allowed without permission in writing from the publisher
去勢抵抗性前立腺癌におけるKlothoγのドセタキセル抵抗性との関連と新規治療としての可能性
Get PDFThe Klotho (KL) gene was first identified as a potent aging suppressor. The KL family currently comprises of three proteins: α-Klotho (KLA), β-Klotho (KLB), and γ-Klotho (KLG). Many studies have shown that KLA and KLB participate in tumor progression or suppression, depending on the type of cancer; however, the relationship between KLG and prostate cancer has not yet been studied. Some studies have claimed that KL is correlated to sensitivity to chemotherapy. Here, we investigated the oncogenic potential of KLG in castration-resistant prostate cancer (CRPC). Immunohistochemical analysis using prostate biopsy specimens revealed that patients with high KLG expression in primary prostate cancer tissue had a significantly poor prognosis for overall survival. In addition, the prostate-specific antigen response rate after docetaxel (DTX) therapy in patients with high KLG expression was lower than that in patients with low KLG expression. To evaluate the potential of KLG as a therapeutic target in human prostate cancer, we generated a xenograft model of human CRPC cell line (PC-3) in male athymic mice. The animals were randomly divided into four groups as follows: i) control group (vehicle only); ii) DTX group (intraperitoneal administration); iii) small interfering RNA targeting KLG (KLG siRNA) group (intratumoral administration); and iv) a combination group (DTX plus KLG siRNA). After 3 weeks of treatment, the tumor weight and tumor Ki-67 labeling index were significantly lower in the KLG siRNA group and the combination group than in the control group. Sensitivity to DTX was increased upon treatment with KLG siRNA. These findings suggest that KLG expression in primary prostate cancer lesions is associated with resistance to DTX in CRPC and has potential as a diagnostic and therapeutic target for patients with CRPC.博士（医学）・甲第740号・令和2年3月16日Copyright: © Onishiet al. This is an open access article distributed under theterms of CreativeCommons Attribution License(https://creativecommons.org/licenses/by-nc-nd/4.0/)
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
Get PDFRenal 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
EGFRvIII特異的キメラ抗原受容体発現NK細胞を用いたGBMに対する新規治療法の開発
No full textBackground/Aim: Natural killer (NK) cells are considered potential antitumor effector cells. The aim of this study was toestablish a novel type of a chimeric antigen receptor (CAR) NK cell line (CAR-KHYG-1) specific for epidermal growth factorreceptor variant III (EGFRvIII)-expressing tumors and investigate the anti-tumor activity of EGFRvIII-specific-CAR-KHYG-1(EvCAR-KHYG-1). Materials and Methods: EvCAR-KHYG-1 was established by self-inactivated lentiviral-based transduction of theEvCAR gene and magnetic bead-based purification of EvCAR-expressing NK cells. The anti-tumor effects of EvCAR-KHYG-1 wereevaluated using growth inhibition and apoptosis detection assays in glioblastoma (GBM) cell lines (EGFRvIII-expressing andnon-expressing U87MG). Results: The findings demonstrated that EvCAR-KHYG-1 inhibited GBM cell-growth via apoptosis in anEGFRvIII-expressing specific manner. Conclusion: This is the first study to establish a CAR NK cell line based on the humanNK cell line KHYG-1. Therapy with EvCAR-KHYG-1 may be an effective treatment option for GBM patients.博士（医学）・甲第726号・令和2年3月16日Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.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://dx.doi.org/10.21873/anticanres.12824"（※全文閲覧は学内限定
アルサニル酸を用いたマウス内耳破壊後の前庭代償過程
Get PDFWhen vestibular function is lost, vestibular compensation works for the reacquisition of body balance. For the study of vestibular dysfunction and vestibular compensation, surgical or chemical labyrinthectomy has been performed in various animal species. In the present study, we performed chemical labyrinthectomy using arsanilic acid in mice and investigated the time course of vestibular compensation through behavioral observations and histological studies. The surgical procedures required only paracentesis and storage of 50 µL of p-arsanilic acid sodium salt solution in the tympanic cavity for 5 min. From behavioral observations, vestibular functions were worst at 2 days and recovered by 7 days after surgery. Spontaneous nystagmus appeared at 1 day after surgery with arsanilic acid and disappeared by 2 days. Histological studies revealed specific damage to the vestibular endorgans. In the ipsilateral spinal vestibular nucleus, the medial vestibular nucleus, and the contralateral prepositus hypoglossal nucleus, a substantial number of c-Fos-immunoreactive cells appeared by 1 day after surgery with arsanilic acid, with a maximum increase in number by 2 days and complete disappearance by 7 days. Taken together, these findings indicate that chemical labyrinthectomy with arsanilic acid and the subsequent observation of vestibular compensation is a useful strategy for elucidation of the molecular mechanisms underlying vestibular pathophysiologies.博士（医学）・甲第742号・令和2年3月16日© 2019 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/)
子宮頸部細胞診で意義不明の異型扇平上皮細胞 (ASC-US) にHPV検査を施行した症例の臨床病理学的検討
No full text【目的】ベセスダ式子宮頸部細胞診報告様式において、意義不明の異型肩平上皮細胞（atypical squamous cells, undetermined significance: ASC-US）は、ほとんどの標本に認められるあいまいな所見が軽度扇平上皮内病変を示唆するものとされる。今回、ASC-US後のhuman papillomavirus(HPV)検査施行例に対して臨床病理学的検討をおこなった。【方法】対象は2013年から2017年の5年間に当科でASC-USの結果後にHPV検査を施行した60症例である。【成績】60例の平均年齢は40.1歳で、追跡期間は平均27.6ヵ月、細胞診回数は平均5.1回、生検回数は平均1.6回であった。HPV検査陽性は36例、陰性は24例であった。初回生検結果はHPV陽性36例で良性が14例、cervical intraepitheilal neoplasia (CIN) 1が11例、CIN 2が4例、CIN 3が4例、生検未施行3例であり、HPV陰性24例は良性が8例、CIN 1が4例、CIN 2が1例、生検未施行が11例であった。継続管理中の生検や細胞診結果を考慮した臨床診断はHPV検査陽性36例で良性が21例、CIN 1が4例、CIN 2が3例、CIN 3が8例であり、陰性24例は全例良性であった。【結論】ASC-USでHPV検査陽性36例中22%にCIN 3を認めたことより陽性例では慎重な継続管理が重要と考えられた。HPV検査陰性例は臨床診断が全て良性であったため、細胞診受診間隔の延長や生検の省略の可能性について検討することが必要と考えた
10cm以上の巨大肝細胞癌に対する、ゼラチンスポンジによる肝動脈塞栓術 (bland TAE) と、Lipiodolと抗癌剤による肝動脈化学塞栓術 (TACE) の併用法の治療効果
No full textIntroduction: To assess the efficacy of combined therapy involving bland transarterial embolization using gelatin sponge particles (bland GS-TAE) followed by transarterial chemoembolization using lipiodol mixed with anticancer agents and GS particles (Lip-TACE) to reduce the adverse events and increase the therapeutic effect of Lip-TACE in the treatment of huge (≥10 cm) hepatocellular carcinoma (HCC).Material and methods: Twenty-one consecutive patients with huge HCCs (≥10 cm in diameter) were enrolled in this study. First, bland GS-TAE was performed to reduce the tumor volume, and then Lip-TACE was performed to control the remaining tumor at intervals of around three weeks. Tumor response, survival, and adverse events of this combined therapy were assessed.Results: The tumor response was assessed three months after combined TACE, with complete response in 38.1% and partial response in 57.1% of cases. Severe adverse events were seen in two patients, acute cholecystitis and tumor rupture. The median survival time was 2.7 years, and the one-, two-, three-, and five-year overall survival rates were 76.2%, 66.7%, 42.9%, and 25.0%, respectively.Conclusion: Combined therapy involving bland GS-TAE followed by Lip-TACE can be performed safety and may improve survival in patients with huge HCCs.博士（医学）・乙第1462号・令和2年6月30日© 2020 Society of Medical Innovation and TechnologyThis is a post-peer-review, pre-copyedit version of an article published in Minimally invasive therapy and allied technologies. The final authenticated version is available online at: https://doi.org/10.1080/13645706.2020.1725580