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卵巣明細胞癌においてHNF-1β -USP28-Claspin pathwayはDNA損傷によるChk1活性化を促進する
Get PDFTranscription factor hepatocyte nuclear factor 1-beta (HNF-1β) enhances checkpoint kinase 1 (Chk1) activation and promotes G2/M cell cycle progression in ovarian clear cell carcinoma (CCC) following exposure to diverse genotoxic agents including bleomycin. However, the underlying mechanism leading to checkpoint activation of HNF-1β still remains largely unknown. To clarify the effects of HNF-1β on cell cycle checkpoints, human CCC cell lines were transfected with siRNAs targeting HNF-1β, Claspin, USP28, or a control vector. Ubiquitination and stabilization of Claspin protein by HNF-1β was assessed by immunoprecipitation. Loss-of-function studies using RNAi-mediated gene silencing indicated that HNF-1β facilitated the Claspin expression after treatment with a genotoxic agent bleomycin, resulting in accumulation of phosphorylated Chk1 (p-Chk1) and promotion of survival in CCC cell lines. This study showed for the first time that USP28, a de-ubiquitinase crucial for Claspin expression, is one target gene of HNF-1β. Knockdown of endogenous USP28 suppressed the Claspin expression and p-Chk1 activation and cell viability. Our findings identify a novel pathway of the HNF-1β-USP28-Claspin-Chk1 axis in checkpoint signal amplification in response to DNA damage. Targeting this pathway may represent a putative, novel, anticancer strategy in ovarian CCC.博士（医学）・乙第1435号・令和元年9月27日Copyright © 2018 Impact Journals, LLCCopyright © Ito et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC
BY 3.0 https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are
credited
炎症性腸疾患におけるREG遺伝子ファミリーの発現と制御
Get PDFThe pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members have been reported to be expressed in Crohn's disease (CD) and ulcerative colitis (UC) and to be involved as proliferative mucosal factors in IBD. However, expression of all REG family genes in IBD is still unclear. Here, we analyzed expression of all REG family genes (REG Iα, REG Iβ, REG III, HIP/PAP, and REG IV) in biopsy specimens of UC and CD by real-time RT-PCR. REG Iα, REG Iβ, and REG IV genes were overexpressed in CD samples. REG IV gene was also overexpressed in UC samples. We further analyzed the expression mechanisms of REG Iα, REG Iβ, and REG IV genes in human colon cells. The expression of REG Iα was significantly induced by IL-6 or IL-22, and REG Iβ was induced by IL-22. Deletion analyses revealed that three regions (- 220 to - 211, - 179 to - 156, and - 146 to - 130) in REG Iα and the region (- 274 to- 260) in REG Iβ promoter were responsible for the activation by IL-22/IL-6. The promoters contain consensus transcription factor binding sequences for MZF1, RTEF1/TEAD4, and STAT3 in REG Iα, and HLTF/FOXN2F in REG Iβ, respectively. The introduction of siRNAs for MZF1, RTEF1/TEAD4, STAT3, and HLTF/FOXN2F abolished the transcription of REG Iα and REG Iβ. The gene activation mechanisms of REG Iα/REG Iβ may play a role in colon mucosal regeneration in IBD.博士（医学）・乙第1438号・令和元年9月27日© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/)
近赤外線スベクトロスコピィを用いた小児期自閉スペクトラム症の前頭前野における血液動態反応の低下
Get PDFBackground: Functional neuroimaging studies suggest that prefrontal cortex dysfunction is present in people with autism spectrum disorder (ASD). Near-infrared spectroscopy is a noninvasive optical tool for examining oxygenation and hemodynamic changes in the cerebral cortex by measuring changes in oxygenated hemoglobin. Methods: Twelve drug-naïve male participants, aged 7-15 years and diagnosed with ASD according to DSM-5 criteria, and 12 age- and intelligence quotient (IQ)-matched healthy control males participated in the present study after giving informed consent. Relative concentrations of oxyhemoglobin were measured with frontal probes every 0.1 s during the Stroop color-word task, using 24-channel near-infrared spectroscopy. Results: Oxyhemoglobin changes during the Stroop color-word task in the ASD group were significantly smaller than those in the control group at channels 12 and 13, located over the dorsolateral prefrontal cortex (FDR-corrected P: 0.0021-0.0063). Conclusion: The results suggest that male children with ASD have reduced prefrontal hemodynamic responses, measured with near-infrared spectroscopy.博士（医学）・乙第1442号・令和元年12月5日© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated
不安定プラークを伴った頚動脈狭窄症に対するクローズセルステントを用いたステントインステント法による頚動脈ステント留置術
Get PDFPurpose: To examine whether carotid artery stenting (CAS) of stenoses with unstable plaque using a closed-cell stent-in-stent technique prevents plaque protrusion. Materials and Methods: Between December 2014 and August 2018, 35 consecutive patients (mean age 75.8 years; 29 men) with carotid artery stenosis (20 symptomatic) and unstable plaque diagnosed by magnetic resonance imaging were prospectively analyzed. Mean diameter stenosis was 83.5%. All CAS procedures were performed with stent-in-stent placement of Carotid Wallstents using an embolic protection device and conservative postdilation. The technical success rate, incidence of plaque protrusion, ischemic stroke rate within 30 days, and new ipsilateral ischemic lesions on diffusion-weighted imaging (DWI) within 48 hours after CAS were prospectively assessed. Follow-up outcomes included the incidences of ipsilateral stroke and restenosis. Results: The technical success rate was 100%. No plaque protrusion or stroke occurred in any patient. New ischemic lesions were observed on DWI in 10 (29%) patients. During the mean 11.6-month follow-up, no ipsilateral strokes occurred. Two (6%) patients developed asymptomatic restenosis recorded as 53% lumen narrowing and occlusion, respectively. Conclusion: CAS using a closed-cell stent-in-stent technique for unstable plaque may be useful for preventing plaque protrusion and ischemic complications.博士（医学）・乙第1444号・令和元年12月5日This is a non-final version of an article published in final form in "https://doi.org/10.1177/1526602819847698
初診後31ヵ月間の継続管理によりserous endometrial intraepithelial carcinomaを検出した1例
Get PDF漿液性子宮内膜上皮内癌(serous endometrialintraepithelial carcinoma,以下SEIC)は、子宮漿液癌の前駆病変と推定され、核のp53過剰発現が特徴で、腹膜播種が多く予後が不良とされる。内膜は菲薄で生検採取量が少なくSEICの術前診断が困難なことが多い。今回、われわれは術前の内膜細胞診がSEICの診断に有用であった一例を経験したので報告する。症例は70歳代女性で、不正出血を主訴に当科を受診した。内膜細胞診は偽陽性で内膜生検が良性のため経過観察となった。当科初診31ヵ月後の液状検体法による内膜細胞診が陽性で、その異型細胞の核はp53染色陽性であった。内膜生検は悪性の断定が困難であったが、術前診断をSEIC疑いとし腹腔鏡下子宮摘出術を施行した。摘出子宮標本の内膜に明らかな肥厚はなく、卵巣卵管に異常所見を認めなかった。摘出標本組織は、表層の上皮は多くを消失し、ごく少数域に核の腫大や核小体の明瞭化を伴った異型腺管が散見され、異型腺管細胞の核はp53染色陽性であった。病理診断はSEICであり術後進行期がpT 1 aNxM 0であった。術後に予防的化学療法が3回施行され、現在術後16ヵ月にて無病生存である。内膜生検単独では術前にSEICの診断を得ることは難しく、内膜細胞診の液状検体でp53染色を併用することが診断の補助になると思われた
プロポフォールは、酸化的ストレス条件下で心筋細胞株H9c2におけるNrf2の発現及び核局在を誘導する
Get PDFOxidative stress contributes to myocardial ischemia-reperfusion injury, which causes cardiomyocyte death and precipitate life-threatening heart failure. Propofol has been proposed to protect cells or tissues against oxidative stress. However, the mechanisms underlying its beneficial effects are not fully elucidated. In the present study, we employed an in vitro oxidative injury model, in which rat cardiac H9c2 cells were treated with H2O2, and investigated roles of propofol against oxidative stress. Propofol treatment reduced H2O2-induced apoptotic cell death. While H2O2 induced expression of the antioxidant enzyme HO-1, propofol further increased HO-1 mRNA and protein levels. Propofol also promoted nuclear localization of Nrf2 in the presence of H2O2. Knockdown of Nrf2 using siRNA suppressed propofol-inducible Nrf2 and expression of Nrf2-downstream antioxidant enzyme. Knockdown of Nrf2 suppressed the propofol-induced cytoprotection. In addition, Nrf2 overexpression induced nuclear localization of Nrf2 and HO-1 expression. These results suggest that propofol exerts antioxidative effects by inducing nuclear localization of Nrf2 and expression of its downstream enzyme in cardiac cells. Finally, we examined the effect of propofol on cardiomyocytes using myocardial ischemia-reperfusion injury models. The expression level of Nrf2 protein was increased at 15 min after reperfusion in the ischemia-reperfusion and propofol group compared with ischemia-reperfusion group in penumbra region. These results suggest that propofol protects cells or tissues from oxidative stress via Nrf2/HO-1 cascade.博士（医学）・甲第696号・平成31年3月15日Copyright: © 2018 Shinjo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License(https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
ラット膀胱での水吸収におけるアクアポリン-2の役割
Get PDFAIM: We investigated the role of the bladder wall in permeating water, focusing on aquaporins. METHODS: Female Sprague-Dawley rats weighing 300 g were used to investigate the role of the bladder wall in saline permeation. Changes in intravesical fluid volume and sodium concentration were measured in the desmopressin acetate hydrate-loaded and control groups 3 h after administration. Bladders were resected to measure aquaporin-1, 2, and 3 gene expression using qRT-PCR. Additionally, the change of aquaporin-2 expression was measured using Western blotting and immunohistochemistry in intravesical aquaporin-2 siRNA-treated and control groups. RESULTS: Although the intravesical fluid volume and sodium concentration significantly decreased from 0 to 3 h (1.00 ± 0.00 vs 0.83 ± 0.08 mL, 157.80 ± 1.30 vs 146.8 ± 1.92 mEq/mL, P < 0.01, respectively in the control group), administration of desmopressin did not affect the extent of volume change. Aquaporin-2 expression was significantly higher in the 3-h distended bladders than in the empty bladder. Aquaporin-2 siRNA treatment suppressed aquaporin-2 expression and the change of intravesical fluid volume from 0 to 3 h (1.00 ± 0.00 and 0.99 ± 0.02 mL), which was related to the suppression of sodium concentration change in comparison with control siRNA treatment (149.6 ± 2.4 vs 143.6 ± 3.67 mEq/mL, P < 0.05). CONCLUSIONS: The rat urinary bladder absorbs water and salts under the full-filled condition. Aquaporin-2 plays an important role in the transport of water, accompanied by sodium concentration change. We demonstrated a part of the bladder absorption mechanism, which may lead to development of a new method for regulating bladder storage function.博士（医学）・甲第697号・平成31年3月15日© 2018 Wiley Periodicals, Inc.This is the pre-peer reviewed version of the following article: [https://onlinelibrary.wiley.com/doi/full/10.1002/nau.23715], which has been published in final form at [http://dx.doi.org/10.1002/nau.23715]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions
フルクトースの経口投与はラット脂肪性肝炎モデルにおいて腸管透過性亢進作用を介して肝線維化および肝発癌を悪化させる
Get PDFRecent reports have revealed the impact of a western diet containing large amounts of fructose on the pathogenesis of non-alcoholic steatohepatitis (NASH). Fructose exacerbates hepatic inflammation in NASH by inducing increasing intestinal permeability. However, it is not clear whether fructose contributes to the progression of liver fibrosis and hepatocarcinogenesis in NASH. The aim of this study was to investigate the effect of fructose intake on NASH in a rat model. A choline-deficient/L-amino acid diet was fed to F344 rats to induce NASH. Fructose was administrated to one group in the drinking water. The development of liver fibrosis and hepatocarcinogenesis were evaluated histologically. Oral fructose administration exacerbated liver fibrosis and increased the number of preneoplastic lesions positive for glutathione S-transferase placental form. Fructose-treated rats had significantly higher expression of hepatic genes related to toll-like receptor-signaling, suggesting that fructose consumption increased signaling in this pathway, leading to the progression of NASH. We confirmed that intestinal permeability was significantly higher in fructose-treated rats, as evidenced by a loss of intestinal tight junction proteins. Fructose exacerbated both liver fibrosis and hepatocarcinogenesis by increasing intestinal permeability. This observation strongly supports the role of endotoxin in the progression of NASH.博士（医学）・乙第1432号・令和元年9月27日Copyright © 2018 Impact Journals, LLCCopyright © Seki et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0
(CC BY 3.0 https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source
are credited
脊椎手術中のMonophasic刺激下での経頭蓋刺激筋誘発電位における定電流刺激と定電圧刺激での比較検討
Get PDFConstant-voltage and constant-current stimulators may be used for transcranial electrical stimulation of motor evoked potentials (TES-MEP). However, no previous report has determined whether the two monophasic stimulation methods lead to similar responses during intra-operative monitoring. We studied differences in the lateralities of compound muscle action potentials (CMAPs) during intra-operative spinal cord monitoring via TES-MEP using monophasic constant-current and constant-voltage stimulations. CMAPs were bilaterally recorded from the upper and lower limb muscles in 95 patients who underwent elective spine and spinal cord surgery. We used two monophasic stimulation patterns: pattern 1, right anode and left cathode; pattern 2, right cathode and left anode. There were no statistically significant differences between the right and left sides with respect to success rates, wave amplitudes, and efficiencies, with constant-voltage stimulation, however, there were statistically significant differences between the right and left sides with constant-current stimulation. In case of our stimulation condition, there were no statistically significant differences between the right and left sides with respect to CMAPs with constant-voltage stimulation; constant-current stimulation was influenced by the type of monophasic stimulation, which necessitates the switch the polarity of the stimulation to bilaterally record CMAPs.博士（医学）・甲第725号・令和元年12月5日© The Author(s) 2019 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 license, and indicate if changes were made. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the
material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/