AN AUTOPSY CASE OF PORTOPULMONARY HYPERTENSION ASSOCIATED WITH ALCOHOLIC LIVER CIRRHOSIS

We report an autopsy case of pulmonary pexogenic arteriopathy associated with portal hypertension due to alcoholic liver cirrhosis, termed portopulmonary hypertension (PPHT). A 49-year-old man who has had alcoholic liver cirrhosis for 10 years complained of severe dyspnea (Fletcher-Hugh-Jones V). Chest CT revealed marked enlargement of bilateral hilar pulmonary arteries and cardiomegaly associated with right ventricular hypertrophy. The patient died from hepatic. encephalopathy and respiratory failure. Autopsy c1early revealed the wall thickness of pulmonary small vessels diffusely in peripheral fields on cut surfaces and marked dilatation of the main pulmonary artery, together with liver cirrhosis. Microscopically, the pulmonary small arteries demonstrated grade 5 pulmonary plexogenic arteriopathy inc1uding plexiform lesions and a micronodule resembling an arachnoid granulation or meningioma throughout the lungs. This case suggested that a typical plexogenic arteriopathy morphologically and definitely contributed to confirm PPHT, although the patient was c1inically suspected of hepatopulmonary syndrome (HPS)

肺高血圧症に対するトロンボキサン合成阻害作用をもった新規長期作用型プロスタサイクリンアゴニストの経口投与

BACKGROUND: Continuous administration of prostacyclin has improved the survival of patients with pulmonary arterial hypertension (PAH). However, this treatment has some problems, including its short duration of activity and difficult delivery. Therefore, we developed ONO-1301, an orally active, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. METHODS AND RESULTS: We investigated whether oral administration of ONO-1301 can both prevent and reverse monocrotaline (MCT)-induced PAH in rats. Rats were randomly assigned to receive repeated oral administration of ONO-1301 twice daily beginning either 1 or 8 days after subcutaneous injection of MCT. A control group received oral saline, and a sham group received a subcutaneous injection of saline instead of MCT. MCT-treated controls developed significant pulmonary hypertension. Treatment with ONO-1301 from day 1 or 8 significantly attenuated the increases in right ventricular systolic pressure and the increase in medial wall thickness of pulmonary arterioles. Kaplan-Meier survival curves demonstrated that the effect of ONO-1301 was equivalent to that of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. A single oral dose of ONO-1301 increased plasma cAMP levels for up to 6h. Treatment with ONO-1301 significantly decreased urinary 11-dehydro-thromboxane B2 and increased the plasma hepatocyte growth factor concentration. CONCLUSIONS: Oral administration of ONO-1301 ameliorated PAH in rats, an effect that may occur through cAMP and hepatocyte growth factor.博士（医学）・乙1326号・平成26年3月17日日本循環器学会の許諾を得て登録（2014年6月6日付）ジャーナル公式サイト（日本循環器学会HP内）：https://www.j-circ.or.jp/journal/公開サイト（J-STAGE）：https://www.jstage.jst.go.jp/browse/circj

ガイコクゴ ノ ガクシュウ キョウジュ ヒョウカ ノ タメ ノ ヨーロッパ キョウツウ サンショウワク (CEF) ノ ニホンゴ キョウイク ニ オケル カツヨウ - ドイツ ・ ベルリンシュウ ノ チュウトウ キョウイク ニホンゴ ガイドライン ノ レイ

ヨーロッパ評議会 (Council of Europe) により開発された言語教育の評価基準である、外国語の学習、教授、評価のためのヨーロッパ共通参照枠(Common European Framework of Lan-guages、以下CEF) と言語学習記録のためのツール、言語ポートフォリオ (European LanguagePortfolio、以下ELP) は、ドイツの学校教育において着実に導入が進んでいる。一例として、2003年、2004年に相次いで策定された、第一外国語の「教育スタンダード」には、CEFの能力モデルが全面的に取り入れられている。ベルリン州では2003/04年度にこの「教育スタンダード」の能力モデルに基づき、全ての外国語科目の中等教育後期用ガイドラインの改訂が行なわれた。 外国語科目のひとつである日本語のガイドラインも、CEF に基づいて改訂され、ドイツの学校における日本語に初めて CEF の基準が適用された。本稿では、まず、このガイドライン開発の契機となった教育スタンダードを概観し、ドイツの教育界が「パラダイムの変化」を遂げようとしている点を指摘する。そして、ヨーロッパ言語を中心に開発されたCEFの外国語能力記述が、中等教育の日本語教育へどのように応用されているかを、ベルリンの日本語ガイドラインの分析を通して明らかにする。最後にこれらの分析を通して、CEFを採用した改訂版日本語ガイドラインが授業の現場と教師、更にドイツの日本語教育に及ぼしうる影響に言及する。また、CEFにみる外国語教育の合理主義への動きと、それと並存しうる人文主義的教育の重要性を指摘し、教師の新たな役割についても論じる。The Council of Europe recently developed the Common European Framework (CEF) of Reference for Languages: Learning, Teaching, and Assessment and the European Language Portfolio (ELP) in order to promote language teaching and learning by setting clear and attainable standards at different levels of language education. The Standing Conference of the Ministers of Education and Cultural Affairs of the federal states in the Federal Republic of Germany (Kultusministerkonferenz, KMK) published the “Educational Standards” in 2003 and 2004 for teaching the first foreign language in secondary schools. These “Educational Standards” clearly state and adopt the competence model from the CEF.The State of Berlin then revised the teaching guidelines for all foreign languages for upper secondary education based on the “Educational Standard” and consequently on the competence model of the CEF in the academic year 2003–04. The revised guidelines for Japanese turned out to be the first implementation of the CEF in the field of Japanese education in Germany.This paper first summarizes the competence model introduced in the “Educational Standard” for foreign languages and points out that the educational system in Germany is facing a “paradigm shift.” We then analyze the Japanese guidelines for Berlin as an example of examining the problems in applying the competence model of the CEF to Japanese language education at the secondary school level, when it was developed mainly for the European languages. Finally, we refer to the possible impact of the revised version of the guidelines for Japanese on the actual lessons, teachers, and over all Japanese language education in Germany. We also argue that adopting the CEF implies a commitment to efficiency-oriented rationalism in the field of foreign language teaching and a discussion on the importance of humanistic education, which may coexist with rationalism, while suggesting new roles for language teachers

Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer

Overcoming cisplatin (CDDP) resistance is a major issue in urothelial cancer (UC), in which CDDP-based chemotherapy is the first-line treatment. WEE1, a G2/M checkpoint kinase, confers chemoresistance in response to genotoxic agents. However, the efficacy of WEE1 blockade in UC has not been reported. MK-1775, a WEE1 inhibitor also known as AZD-1775, blocked proliferation of UC cell lines in a dose-dependent manner irrespective of TP53 status. MK-1775 synergized with CDDP to block proliferation, inducing apoptosis and mitotic catastrophe in TP53-mutant UC cells but not in TP53-WT cells. Knocking down TP53 in TP53-WT cells induced synergism of MK-1775 and CDDP. In UMUC3 cell xenografts and two patient-derived xenograft lines with MDM2 overexpression, in which the p53/cell cycle pathway was inactivated, AZD-1775 combined with CDDP suppressed tumor growth inducing both M-phase entry and apoptosis, whereas AZD-1775 alone was as effective as the combination in RT4 cell xenografts. Drug susceptibility assay using an ex vivo cancer tissue-originated spheroid system showed correlations with the in vivo efficacy of AZD-1775 alone or combined with CDDP. We determined the feasibility of the drug susceptibility assay using spheroids established from UC surgical specimens obtained by transurethral resection. In conclusion, WEE1 is a promising therapeutic target in the treatment of UC, and a highly specific small molecule inhibitor is currently in early phase clinical trials for cancer. Differential antitumor efficacy of WEE1 blockade alone or combined with CDDP could exist according to p53/cell cycle pathway activity, which might be predictable using an ex vivo 3D primary culture system

Ezrin interacts with the SARS coronavirus spike protein and restrains infection at the entry stage

© 2012 Millet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Entry of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and its envelope fusion with host cell membrane are controlled by a series of complex molecular mechanisms, largely dependent on the viral envelope glycoprotein Spike (S). There are still many unknowns on the implication of cellular factors that regulate the entry process. Methodology/Principal Findings: We performed a yeast two-hybrid screen using as bait the carboxy-terminal endodomain of S, which faces the cytosol during and after opening of the fusion pore at early stages of the virus life cycle. Here we show that the ezrin membrane-actin linker interacts with S endodomain through the F1 lobe of its FERM domain and that both the eight carboxy-terminal amino-acids and a membrane-proximal cysteine cluster of S endodomain are important for this interaction in vitro. Interestingly, we found that ezrin is present at the site of entry of S-pseudotyped lentiviral particles in Vero E6 cells. Targeting ezrin function by small interfering RNA increased S-mediated entry of pseudotyped particles in epithelial cells. Furthermore, deletion of the eight carboxy-terminal amino acids of S enhanced S-pseudotyped particles infection. Expression of the ezrin dominant negative FERM domain enhanced cell susceptibility to infection by SARS-CoV and S pseudotyped particles and potentiated S-dependent membrane fusion. Conclusions/Significance: Ezrin interacts with SARS-CoV S endodomain and limits virus entry and fusion. Our data present a novel mechanism involving a cellular factor in the regulation of S-dependent early events of infection.This work was supported by the Research Grant Council of Hong Kong (RGC#760208)and the RESPARI project of the International Network of Pasteur Institutes

Fluid flow-induced left-right asymmetric decay of Dand5 mRNA in the mouse embryo requires a Bicc1-Ccr4 RNA degradation complex

Molecular left-right (L-R) asymmetry is established at the node of the mouse embryo as a result of the sensing of a leftward fluid flow by immotile cilia of perinodal crown cells and the consequent degradation of Dand5 mRNA on the left side. We here examined how the fluid flow induces Dand5 mRNA decay. We found that the first 200 nucleotides in the 3′ untranslated region (3′-UTR) of Dand5 mRNA are necessary and sufficient for the left-sided decay and to mediate the response of a 3′-UTR reporter transgene to Ca2+, the cation channel Pkd2, the RNA-binding protein Bicc1 and their regulation by the flow direction. We show that Bicc1 preferentially recognizes GACR and YGAC sequences, which can explain the specific binding to a conserved GACGUGAC motif located in the proximal Dand5 3′-UTR. The Cnot3 component of the Ccr4-Not deadenylase complex interacts with Bicc1 and is also required for Dand5 mRNA decay at the node. These results suggest that Ca2+ currents induced by leftward fluid flow stimulate Bicc1 and Ccr4-Not to mediate Dand5 mRNA degradation specifically on the left side of the node