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Promoter Working Group 7082
No full text: Promoter working group was created in september 1992 under the umbrella, and with a three-years funding, of the Esprit III program in Basic Research. Its main objective is to strengthen and organize European software process modelling research. This document reports the work done during the project. Keywords: Software process concepts, Process modeling, Architecture of PSEE, Performance, enactment, metaprocess. PROMOTER documents with status INTERNAL_DRAFT or DRAFT are to be circulated only within the PROMOTER project team. Documents with status PROVISIONAL may be circulated beyond the project team, but only as explicitly approved by the Change Authority. Circulation of documents with status FINAL is unrestricted. Promoter Working Group 7082 Promoter Final report Page 2 of99 Promoter Working Group 7082 Promoter Final report Page 3 of99 A: Content A SYNOPSIS 5 B Books writen by Promoter 9 B.1 First book 9 B.2 Promoter Second Book 9 C EWSPT Reports 11 C.1 EWSPT'i organisation..
Study of the anti-cancer effect and mechanism of NF-κB inhibitor, Bay11-7082
No full textXAV939, which stabilizes the structure of axin, was developed as an anti-cancer drug to inhibit Wnt/β-catenin signaling pathway. In some cases, increased axin expression results in resistance to various anti-cancer drugs. To overcome this, we attempted to identify alternative drugs that are effective against XAV939-resistant cells. To that end, we screened various inhibitors and found that the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling reduces cell viability in association with a reduction in axin and β-catenin expression. Among the inhibitors, Bay11-7082 (Bay) was the most effective. Subsequent analysis revealed that Bay treatment, but not other NF-κB signaling inhibitors, induced proteasomal degradation of axin, β-catenin, and GSK-3β which might result in the reduction of Wnt signaling activity. This additional Bay11-7082 activity appeared to be more effective on cells with high Wnt activity, such as adenocarcinoma gastric cell line (AGS) cells. Cells (EC96) with suppressed Wnt signaling and high NF-κB signaling did not show proteasomal degradation of axin, β-catenin, and GSK-3β. Nevertheless, Bay11-7082 reduced the viability of two cells—AGS and EC96. Moreover, axin-expressing HeLa (HeLa-axin) showed reduced cell viability after Bay11-7082 treatment but not with XAV939, which suggested the efficient effect of Bay11-7082 on axin-expressing cells. Our results suggest that Bay11-7082 can be an effective anti-cancer agent against XAV939-resistant cancer cells. ;Wnt/b-catenin signaling을 inhibition 하기 위한 anti-cancer drug 으로 axin structure를 안정화시키는 tankyrase inhibitor XAV939가 개발되었다. 여러사례에서, axin expression 의 증가는 다양한 anti-cancer drug 에 대해 resistance을 초래한다. 이를 해결하기위해, XAV939-resistant cell 에 효과적인 다른 drug을 찾고자 하였다. 다양한 inhibitor 들을 drug screening을 통해 선별하였고, 그 중 NF-kB signaling 의 inhibition이 axin 과 b-catenin expression 의 감소와 관련되어 있고, cell viability 도 효과적으로 감소시켰다. NF-kB signaling을 inhibition 하는 inhibitor 들 중에서, Bay11-7082 (Bay) 가 가장 효과적이었다. 다른 analysis 들을 통해 NF-kB signaling inhibitor 들이 아닌 Bay11-7082 를 처리했을 때, axin와 b-catenin 그리고 GSK3b 을 더욱 효과적으로 proteosomal degradation 시켰고, Wnt signaling activity를 감소 시킬 수 있다는 Bay11-7082 의 다른 effect 을 확인할 수 있었다. Bay11-7082 의 additional effect 는 AGS cell 과 같이 Wnt activity 가 높은 cell 에서 더 효과적이다. EC96 cell 은 Wnt signaling 이 억제되어 있고 NF-kB signaling 이 증가되어 있어 axin와 b-catenin 그리고 GSK3b 의 proteasomal degradation 을 보이지 않는다. 그럼에도 불구하고, Bay11-7082 는 AGS 와 EC96 의 cell viability 를 감소시킨다. 게다가 axin expressing HeLa (HeLa-axin) 은 XAV939 가 아닌 Bay11-7082 처리에 의해 cell viability 가 감소되었고, 이는 axin expressing cell 에서 Bay11-7082 의 효과적인 영향을 보여주었다. 따라서 이러한 결과들은 Bay11-7082 가 XAV939 resistant cancer cell을 위한 anti-cancer agent 의 효과적인 예가 될 수 있음을 시사한다.Ⅰ. Introduction 5
Ⅱ. Materials and Methods 15
1. Cell culture 15
2. Antibodies 15
3. Cell counting with Hemocytometer 15
4. Cell Proliferation assay 16
5. Immunoblot analysis 16
6. Nuclear/Cytoplasmic Fraction 17
7. Immunofluorescence analysis 17
8. Statistical analysis 18
Ⅲ. Results 19
1. Inhibition of NF-kB signaling effectively reduces cancer cell viability 19
2. Triptolide, Celastrol, and Bay11-7082 inhibits NF-kB nuclear translocation 21
3. Bay11-7082 reduces axin and β-catenin expression in HeLa, HeLa-XAV and HeLa-axin cells 23
4. Bay11-7082 induces proteasomal degradation of axin and β-catenin 25
5. Bay11-7082-induced proteasomal degradation is not associated with GSK3β activity 27
6. NF-kB signaling inhibition and proteasomal degradation are separate pharmacological effects of Bay11-7082 29
7. Bay11-7082 is effective anti-cancer agent for cancer cells, including XAV939-resistant cells 34
Ⅳ. Discussion 36
Ⅴ. References 47
Ⅵ. Abstract (in Korean) 6
Exploration of BAY 11-7082 as a Potential Antibiotic
No full textExposure of the Gram-negative
pathogen Pseudomonas
aeruginosa to subinhibitory concentrations of antibiotics
increases the formation of biofilms. We exploited this phenotype to
identify molecules with potential antimicrobial activity in a biofilm-based
high-throughput screen. The anti-inflammatory compound BAY 11-7082
induced dose-dependent biofilm stimulation, indicative of antibacterial
activity. We confirmed that BAY 11-7082 inhibits the growth of P. aeruginosa and other priority pathogens, including
methicillin-resistant Staphylococcus aureus (MRSA). We synthesized 27 structural analogues, including a series
based on the related scaffold 3-(phenylsulfonyl)-2-pyrazinecarbonitrile
(PSPC), 10 of which displayed increased anti-Staphylococcal activity. Because the parent molecule inhibits the NLR Family Pyrin
Domain Containing 3 (NLRP3) inflammasome, we measured the ability
of select analogues to reduce interleukin-1β (IL-1β) production
in mammalian macrophages, identifying minor differences in the structure–activity
relationship for the anti-inflammatory and antibacterial properties
of this scaffold. Although we could evolve stably resistant MRSA mutants
with cross-resistance to BAY 11-7082 and PSPC, their lack of shared
mutations suggested that the two molecules could have multiple targets.
Finally, we showed that BAY 11-7082 and its analogues synergize with
penicillin G against MRSA, suggesting that this scaffold may serve
as an interesting starting point for the development of antibiotic
adjuvants
The expression level of nuclear NF-κB in BAY 11–7082 treated C6 cell.
No full text(A) Cytotoxicity of BAY 11–7082 to C6 cells. (B) Western blot showed that the expression level of CXCL1 in the BAY 11–7082 treated group and the control group. (C) The statistical results of (A). (*PP (TIF)</p
The mechanism of Bay 11-7082-induced MM cell death involves necrosis.
No full text<p>(A) MM.1S and KMS-12-BM cells were treated with 30 µM Bay 11-7082 and analyzed by time-lapse video microscopy. Pictures shown represent typical stages of cells undergoing Bay 11-7082-induced cell death within 3 h. (B) Cells were pretreated for 30 min with BHA (50 µM), necrostatin-1 (90 µM) or remained untreated and were then challenged with 30 µM Bay 11-7082 for 2 h. Cells were finally photographed (B, arrows indicate swollen cells and the plasma membrane). (C) MM cells were either left untreated or pretreated for 1 h with BHA (50 µM), necrostatin-1 (90 µM), z-VAD-fmk (100 µM) or both necrostatin-1 and z-VAD-fmk. Cells were then challenged with 15 µM Bay 11-7082 for 1 h (KMS-12-BM) or 2 h (MM.1S) followed by annexin V-FITC/PI staining and FACS analysis. (D) MM.1S and KMS-12-BM cells were pretreated in triplicates for 30 min with the indicated combinations of BHA (50 µM), necrostatin-1 (90 µM) and z-VAD-fmk (100 µM), exposed for 2 h to 30 µM Bay 11-7082 and then analyzed for viability using the MTT assay. For statistical analysis a one-way ANOVA with a Tukey post-test was performed. Experimental settings that display significant protection against Bay 11-7082 induced cell death (p-values≤0.01) are indicated by asterisks.</p
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
The anti-inflammatory drug BAY 11-7082 suppresses the MyD88-dependent signalling network by targeting the ubiquitin system
Get PDFThe compound BAY 11-7082 inhibits I?Ba [inhibitor of NF-?B (nuclear factor ?B)a] phosphorylation in cells and has been used to implicate the canonical IKKs (I?B kinases) and NF-?B in >350 publications. In the present study we report that BAY 11-7082 does not inhibit the IKKs, but suppresses their activation in LPS (lipopolysaccharide)-stimulated RAW macrophages and IL (interleukin)-1-stimulated IL-1R (IL-1 receptor) HEK (human embryonic kidney)-293 cells. BAY 11-7082 exerts these effects by inactivating the E2-conjugating enzymes Ubc (ubiquitin conjugating) 13 and UbcH7 and the E3 ligase LUBAC (linear ubiquitin assembly complex), thereby preventing the formation of Lys63-linked and linear polyubiquitin chains. BAY 11-7082 prevents ubiquitin conjugation to Ubc13 and UbcH7 by forming a covalent adduct with their reactive cysteine residues via Michael addition at the C3 atom of BAY 11-7082, followed by the release of 4-methylbenzene-sulfinic acid. BAY 11-7082 stimulated Lys48-linked polyubiquitin chain formation in cells and protected HIF1a (hypoxia-inducible factor 1a) from proteasomal degradation, suggesting that it inhibits the proteasome. The results of the present study indicate that the anti-inflammatory effects of BAY 11-7082, its ability to induce B-cell lymphoma and leukaemic T-cell death and to prevent the recruitment of proteins to sites of DNA damage are exerted via inhibition of components of the ubiquitin system and not by inhibiting NF-?B
Effect of BAY11-7082 on MDA-MB-231BR as an NF-κB inhibitor.
No full text(A) Cytotoxicity of 5-FU to MDA-MB-231BR in the presence of 1 μM BAY11-7082. Blue broken lines parallel to x-axis represent the cell viability of MDA-MB-231 (Parent) treated with 30 μM 5-FU. Data represent the mean with SEM of four independent samples. (B) Changes in protein expressions of COX-2 and BCL2A1 in MDA-MB-231BR in response to 1 μM BAY11-7082.</p
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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