Licochalcone A Potently Inhibits Tumor Necrosis Factor ␣- Induced Nuclear Factor-B Activation through the Direct Inhibition of IB Kinase Complex Activation

ABSTRACT Glycyrrhiza inflata has been used as a traditional medicine with anti-inflammatory activity; however, its mechanism has not been fully understood. Licochalcone A is a major and biogenetically characteristic chalcone isolated from G. inflata. Here, we found that licochalcone A strongly inhibited tumor necrosis (TNF)-␣-induced nuclear localization, DNA binding activity, and the transcriptional activity of nuclear factor-B (NF-B). Whereas licochalcone A had no effect on the recruitment of receptor-interacting protein 1 and IB kinase ␤ (IKK␤) to TNF receptor I by TNF-␣, it significantly inhibited TNF-␣-induced IB kinase complex (IKK) activation and inhibitor of nuclear factor-B degradation. It is interesting that we found that the cysteine residue at position 179 of IKK␤ is essential for licochalcone A-induced IKK inhibition, because licochalcone A failed to affect the kinase activity of the IKK␤ (C179A) mutant. In contrast, a structurally related compound, echinatin, failed to inhibit TNF-␣-induced IKK activation and NF-B activation, suggesting that the 1,1-dimethy-2-propenyl group in licochalcone A is important for the inhibition of NF-B. In addition, TNF-␣-induced expression of inflammatory cytokines CCL2/ monocyte chemotactic protein-1and CXCL1/KC was clearly inhibited by licochalcone A but not echinatin. Taken together, licochalcone A might contribute to the potent anti-inflammatory effect of G. inflata through the inhibition of IKK activation

講義科目でアクティブ・ラーニングを可能にする基本構造 : 社会福祉専門職教育関連科目における実践から

社会福祉関連講義科目の教授法の改善として,1年次必修科目「老人福祉論」,「障害者福祉論」の2科目で,課題や試験の評価方法を明記した「ルーブリック」と,毎回の課題として講義ポイントを学生が記入する「ワークシート」を導入した授業デザインを実施した。獲得が期待される行動は「学習習慣の定着」である。2ヶ月間試行後の中間評価として,出席率,ワークシート提出率,ワークシート評価を分析したところ,(1)学生の授業への取り組みが真剣になり,ノートの取り方が向上した, (2)途中まではいい加減に参加していた学生も,小テストの結果やルーブリックの厳密性を認識するにつれて真剣な学習者に変化した,(3)初年次で教員の要求水準を明確に示すことの重要性を明らかにした,という結果を得ることができた。In this article teaching lecture courses utilizing structured assessment for learning is introduced, which is proved effective to make students participate more actively in lecture. Our practice includes using rubrics to show clear expectations and evaluation criteria, assigning the students to work on a guided worksheet for every class, and giving feedback on their work on the sheet every week. The data was collected from the students enrolled in two required, lecture-based courses: "Welfare for the Elderly" and "Welfare for the People with Disability". The following results were observed: 1)Students became more focused and involved in lecture; consequently they learned to take better notes; 2)Students who were disconnected for the first few weeks became serious learners, as they recognize the expectations of the courses and rigid assessment, by receiving feedback on their tests and worksheet every week; and 3)First-year students were more engaged in work and have clearer understanding of expectations than upper-class students, which emphasizes the importance of setting and showing high expectations clearly to the students in their first year

High energy electron observation by Polar Patrol Balloon flight in Antarctica

We accomplished a balloon observation of the high-energy cosmic-ray electrons in 10-1000GeV to reveal the origin and the acceleration mechanism. The observation was carried out for 13 days at an average altitude of 35km by the Polar Patrol Balloon (PPB) around Antarctica in January 2004. The detector is an imaging calorimeter composed of scintillating-fiber belts and plastic scintillation counters sandwiched between lead plates. The geometrical factor is about 600cm^2sr, and the total thickness of lead absorber is 9 radiation lengths. The performance of the detector has been confirmed by a test flight at the Sanriku Balloon Center and by an accelerator beam test using the CERN-SPS (Super Proton Synchrotron at CERN). The new telemetry system using the Iridium satellite, the power system supplied by solar panels and the automatic flight level control operated successfully during the flight. We collected 5.7×10^3 events over 100GeV, and selected the electron candidates by a preliminary data analysis of the shower images. We report here an outline of both detector and observation, and the first result of the electron energy spectrum over 100GeV obtained by an electronic counter

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6–8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response

The Influx And Exodus Of Migrants Among The 47 Prefectures In Japan, 1920-1935.

PhDSociologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/182062/2/5803684.pd

Complete regression of human malignant mesothelioma xenografts following local injection of midkine promoter-driven oncolytic adenovirus

BACKGROUND: Malignant mesothelioma is a highly aggressive tumor with poor prognosis. Conventional therapies for mesothelioma are generally non-curative, and new treatment paradigms are urgently needed. We hypothesized that the tumor-specific midkine (Mdk) promoter could confer transcriptional targeting to oncolytic adenoviruses for effective treatment of malignant mesothelioma. METHODS: We analyzed Mdk expression by quantitative RT-PCR in six human mesothelioma cell lines, and tested Mdk promoter activity by luciferase reporter assay. Based on these data, we constructed a replication-selective oncolytic adenovirus, designated AdMdk-E1-iresTK, which contains an Mdk promoter-driven adenoviral E1 gene and HSV-thymidine kinase (TK) suicide gene, and CMV promoter-driven green fluorescent protein (GFP) marker gene. Selectivity of viral replication and cytolysis were characterized in normal vs. mesothelioma cells in vitro, and intratumoral spread and antitumor efficacy were investigated in vivo. RESULTS: Mdk promoter activity was restricted in normal cells, but highly activated in mesothelioma cell lines. AdMdk-E1-iresTK was seen to efficiently replicate, produce viral progeny, and spread in multiple mesothelioma cell lines. Lytic spread of AdMdk-E1-iresTK mediated efficient killing of these mesothelioma cells, and its in vitro cytocidal effect was significantly enhanced by treatment with the prodrug, ganciclovir. Intratumoral injection of AdMdk-E1-iresTK caused complete regression of MESO4 and MSTO human mesothelioma xenografts in athymic mice. In vivo fluorescence imaging demonstrated intratumoral spread of AdMdk-E1-iresTK-derived signals, which vanished after tumor eradication. CONCLUSIONS: These data indicate that transcriptional targeting of viral replication by the Mdk promoter represents a promising general strategy for oncolytic virotherapy of cancers with upregulated Mdk expression, including malignant mesothelioma