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The gene TP53, encoding p53, has a common sequence polymorphism that results in either proline or arginine at amino-acid position 72. This polymorphism occurs in the proline-rich domain of p53, which is necessary for the protein to fully induce apoptosis. We found that in cell lines containing inducible versions of alleles encoding the Pro72 and Arg72 variants, and in cells with endogenous p53, the Arg72 variant induces apoptosis markedly better than does the Pro72 variant. Our data indicate that at least one source of this enhanced apoptotic potential is the greater ability of the Arg72 variant to localize to the mitochondria; this localization is accompanied by release of cytochrome c into the cytosol. These data indicate that the two polymorphic variants of p53 are functionally distinct, and these differences may influence cancer risk or treatment.

No consensus exists so far on the definition of cellular senescence. The narrowest definition of senescence is irreversible growth arrest triggered by telomere shortening counting cell generations (definition 1). Other authors gave an enlarged functional definition encompassing any kind of irreversible arrest of proliferative cell types induced by damaging agents or cell cycle deregulations after overexpression of proto-oncogenes (definition 2). As stress increases, the proportion of cells in “stress-induced premature senescence-like phenotype” according to definition 1 or “stress-induced premature senescence,” according to definition 2, should increase when a culture reaches growth arrest, and the proportion of cells that reached telomere-dependent replicative senescence due to the end-replication problem should decrease. Stress-induced premature senescence-like phenotype and telomere-dependent replicatively senescent cells share basic similarities such as irreversible growth arrest and resistance to apoptosis, which may appear through different pathways. Irreversible growth arrest after exposure to oxidative stress and generation of DNA damage could be as efficient in avoiding immortalisation as “telomere-dependent” replicative senescence. Probabilities are higher that the senescent cells (according to definition 2) appearingin vivoare in stress-induced premature senescence rather than in telomere-dependent replicative senescence. Examples are given suggesting these cells affectin vivotissue (patho)physiology and aging.

The PEA3 group members PEA3, ER81 and ERM, which are highly conserved transcription factors from the Ets family, are over-expressed in metastatic mammary tumors. In the current study, we present the characterization of a transgenic mouse strain which over-expresses ER81 in the mammary gland via the long terminal repeat of the mouse mammary tumor virus (LTR-MMTV). Although six genotypically positive transgenic lines were identified, only one expressed the ectopic transcript with an exclusive expression in the lactating and late-pregnancy (18th day) mammary glands. No mammary tumor or mammary deregulation appeared after 2 years of ectopic ER81 expression following lactation. We then sought to identify ER81 target genes, and the urokinase plasminogen activator (uPA) and the stromelysin-1, two enzymes involved in extracellular matrix degradation, were found to be transcriptionally upregulated in lactating mammary glands over-expressing ER81. Since these enzymes are involved in metastasis, this murine model could be further used to enhance mammary cancer metastatic process by crossing these animals with mice carrying non-metastatic mammary tumors. We thus created a transgenic mouse model permitting the over-expression of a functionally active Ets transcription factor in the mammary gland without perturbing its development.

9003 Background: Benefit coming from maintenance treatment appears greater for switch maintenance in pts with disease stabilization (SD) while it might be larger for continuation maintenance in pts with objective response (OR). This study assessed a maintenance strategy conditioned by response to cisplatin-gemcitabine (CG): continuation maintenance with G for pts with OR and switch maintenance with pemetrexed (P) for pts with SD compared with a control arm using P continuation maintenance following cisplatin-pemetrexed (CP) induction regimen. Methods: Eligibility criteria included age 18-70 years, PS of 0-1, untreated stage IV NSQ NSCLC without EGFR mutation or ALK rearrangement, ineligibility to bevacizumab. Pts were randomized 1:1 to receive either experimental CG arm: CG (4 cycles) followed by G maintenance in case of OR followed by second-line P or switch maintenance with P for pts with SD, or standard CP arm: 4 cycles CP induction regimen followed by maintenance P. Overall survival (OS) was the primary endpoint; secondary endpoints included PFS, response rate and safety. Results: Between Jul 2012 and Jun 2016, 932 pts were randomized (CG: 467, CP: 465). Pts characteristics were balanced between the arms. 255 pts (54.6%) in the CG arm received maintenance treatment (G: 142, P: 113) while 274 pts (58.9%) received P maintenance in the CP arm. Median number of maintenance cycles was 5 for G and 4 for P in both arms. The OS adjusted HR was 0.97 (95% CI 0.84, 1.13; p=0.72); median OS: 10.9m CG vs. 10.4m CP. The HR for PFS was 0.96 (95% CI 0.84, 1.10; p=0.56); median PFS: 5.0m CG vs. 4.7m CP. Safety profile was as expected during induction chemotherapy. During maintenance, grade ≥3 hematological AEs occurred in 28% and 31% of pts in CG and CP, respectively, with febrile neutropenia (2.4% vs. 1.1%), anemia (9.4% vs. 11.7%), thrombocytopenia (6.7% vs. 5.8%). No grade ≥3 non-hematological AEs occurred in >5% of pts except for asthenia (3.9% CG vs. 5.1% CP). Conclusions: Adapting maintenance strategy according to response to induction chemotherapy does not improve patient outcome. Clinical trial information: NCT01631136.

WI-38 human diploid fibroblasts underwent accelerated telomere shortening (490 bp/stress) and growth arrest after exposure to four subcytotoxic 100 microM tert-butylhydroperoxide (t-BHP) stresses, with a stress at every two population doublings (PD). After subcytotoxic 160 microM H2O2 stress or five repeated 30 microM t-BHP stresses along the same PD, respectively a 322 +/- 55 and 380 +/- 129 bp telomere shortening was observed only during the first PD after stress. The percentage of cells resuming proliferation after stress suggests this telomere shortening is due to the number of cell divisions accomplished to reach confluence during the first PD after stress.

No alternative in vitro method exists fordetecting the potential long-term genotoxic effects ofmolecules at subcytotoxic concentrations, in terms ofdays and weeks after exposure(s) to the moleculetested. A theoretical model of cellular senescence ledto the concept that subcytotoxic stresses under anymolecules at subcytotoxic doses, such as moleculesunder development in the pharmaceutical, cosmetics andfood industry, might lead human fibroblasts into a stateclosely related to in vitro senescence. Thisconcept was then experimentally confirmed invitro: many biomarkers of replicative senescence ofhuman fibroblasts were found 72 h after theirexposure to various kinds of stressors used at non-cytotoxic concentrations. This phenomenon has beentermed stress-induced premature senescence (SIPS).Moreover, proteomics studies have revealed that,besides their effects on the appearance of thebiomarkers of senescence, sublethal stresses under avariety of stressors also lead to long-term specificchanges in the expression level of proteins which arestress-specific. These changes have been coined themolecular scars of stress. The proteins correspondingto these molecular scars may be identified using thelatest developments in mass spectrometry. This modelof stress-induced premature senescence may be appliedto the toxicological sciences when testing for thepotential irreversible long-term effects of moleculeson the cell fate.

1. Parliamentary elite formation after communism: an introduction ELENA SEMENOVA, MICHAEL EDINGER, AND HEINRICH BEST Part I: Central European Parliaments 2. The Czech parliament on the road to professionalization and stabilization ZDENKA MANSFELDOVA 3. Hungarian MPs in the context of political transformation GABRIELLA ILONSZKI AND ANDRAS SCHWARCZ 4. The Polish Diet since 1989: from fragmentation to consolidation JACEK WASILEWSKI AND WITOLD BETKIEWICZ Part II: Baltic 5. Parliaments Recruitment of parliamentary representatives in an ethno-liberal democracy: Estonia MINDAUGAS KUKLYS 6. Legislative elites in multi-ethnic Latvia after 1990 MINDAUGAS KUKLYS 7. Lithuanian parliamentary elites after 1990: dilemmas of political representation and political professionalism IRMINA MATONYTE AND GINTARAS SUMSKAS 8. Croatian parliamentary elites: towards professionalization and homogenization VLASTA ILISIN and GORAN CULAR 9. The 'waiting room': Romanian parliament after 1989 LAURENTIU STEFAN AND RAZVAN GRECU Part III: Post-Soviet Parliaments 10. Legislative elite formation in Moldova: continuity and change WILLIAM CROWTHER 11. Parliamentary representation and MPs in Russia: historical retrospective and comparative perspective OXANA GAMAN-GOLUTVINA 12. Parliamentary representation in post-communist Ukraine: change and stability ELENA SEMENOVA 13. Patterns of parliamentary elite recruitment in post-communist Europe: a comparative analysis ELENA SEMENOVA, MICHAEL EDINGER, AND HEINRICH BEST

The Ets family transcription factor Pea3 (ETV4) is involved in tumorigenesis especially during the metastatic process. Pea3 is known to induce migration and invasion in mammary epithelial cell model systems. However, the molecular pathways regulated by Pea3 are still misunderstood. In the current study, using in vivo and in vitro assays, Pea3 increased the morphogenetic and tumorigenic capacity of mammary epithelial cells by modulating their cell morphology, proliferation, and migration potential. In addition, Pea3 overexpression favored an epithelial–mesenchymal transition (EMT) triggered by TGF-β1. During investigation for molecular events downstream of Pea3, Cyclin D2 (CCND2) was identified as a new Pea3 target gene involved in the control of cellular proliferation and migration, a finding that highlights a new negative regulatory loop between Pea3 and Cyclin D2. Furthermore, Cyclin D2 expression was lost during TGF-β1–induced EMT and Pea3-induced tumorigenesis. Finally, restored Cyclin D2 expression in Pea3-dependent mammary tumorigenic cells decreased cell migration in an opposite manner to Pea3. As such, these data demonstrate that loss of the negative feedback loop between Cyclin D2 and Pea3 contributes to Pea3-induced tumorigenesis. Implications: This study reveals molecular insight into how the Ets family transcription factor Pea3 favors EMT and contributes to tumorigenesis via a negative regulatory loop with Cyclin D2, a new Pea3 target gene. Mol Cancer Res; 11(11); 1412–24. ©2013 AACR.

Mobile communication satellite systems have regularly made the headlines of space industry publications in the 1990s. This paper adopts a new perspective—how the systems evolve over time—to describe the main technical features of the two main types: • -big LEO systems with voice capabilities: Iridium, Globalstar, Odyssey, Inmarsat P21 • -little LEO non-voice systems: Orbcomm, Starsys. This approach reveals the considerable changes, even upheavals, that have affected the design of system components. The apparent stability in the designs is due to outside observers gradually and perhaps unquestioningly perceiving the changes. People's capacity to forget, compounded by the attraction of innovation, may also have a lot to do with it. We present the likely causes of these changes: regulatory environment, market forces, financial arrangements, being at the early design stage, etc. We also analyze the effects of these forces on the systems, and deduce the general trends.

5-Fluorouracil (5-FU) seco-nucleosides having as the 'sugar' moiety a two- carbon (C 2) side chain carrying a N-(2-chloroethyl)-N-nitrosourea group were designed as molecular combinations of antimetabolite and alkylating agent, but hydrolytic release of free 5-FU was not fast enough for significant contribution to the high activity they showed against colon and breast tumors in mice. In the present study of the synthesis of the more reactive C 3 seco- nucleosides, it emerged that, of various groups attached to the aldehydic center in the precursor phthalimides, only the alkoxy/uracil-1-yl type was conveniently obtained by the standard method. The methylthio/uracil-1-yl analog required relatively large amounts of reagent methanethiol, and exploration of alternatives involving α-chlorination of alkyl methyl sulfide or Pummerer rearrangement of its S-oxide, or successive hydrolysis and methylation of isothiouronium bromide, gave disappointing yields. For successful preparation of the alkoxy/uracil-3-yl compounds, the route used for C 2 homologs required considerable experimental modification. In addition to these O,N- and S,N-acetals, some N,N-acetals bearing two 5-FU residues were prepared. The new drugs have been tested against a panel of experimental tumors in mice. Although it is evident from a parallel study that even these C 3 seco-nucleosides release free 5-FU too slowly in vivo, several of them have shown impressive anticancer activity. Reviewing their performance in comparison with earlier molecular combinations, a short list of seven [B.4152 (6), B.4015 (5), B.4030 (10), B.3999 (4), B.3995 (2), B.4083 (3), and B.3996 (the N 3-substituted analog of 1)] should be investigated further. This is particularly appropriate in light of the present understanding of the mode of action of chloroethylating agents. Following a prolonged period of clinical impatience with nitrosoureas because of limited selectivity of action, a new era is confidently anticipated as these powerful drugs are increasingly studied in combination with O 6-benzylguanine and other more efficient inhibitors of repair enzymes like O 6-alkylguanine-DNA-alkyltransferase now being developed.

9077Background: Pemetrexed (Pem) + Cisplatine (Cis) + Bevacizumab (Bev) followed with maintenance therapy (Bev and/or Pem) is a therapeutic standard in advanced non-squamous NSCLC. Methods: A singl...

9005Background: Adding bevacizumab to weekly paclitaxel (wPB) has shown synergistic effect and increased activity in various tumor types. The ULTIMATE study evaluated wPB vs. docetaxel (DOC) as 2nd or 3rd-line treatment in patients with advanced non-squamous NSCLC. Methods: Patients with non-squamous NSCLC progressing after 1 or 2 lines of treatment including platinum-based chemotherapy were randomized 2:1 (stratified by PS, previous lines, prior exposure to bevacizumab) to wPB (paclitaxel 90 mg/m² D1, 8, 15 and bevacizumab 10 mg/kg D1, 15, q28d) or DOC (75 mg/m² q21d) until progression. Patients were allowed to cross-over to the other arm following progression. The primary endpoint was progression-free survival (PFS). Results: From 05/2013 to 08/2014, 166 patients were randomized (wPB: 111, DOC: 55). Clinical characteristics were balanced between both arms. 31% had received previous bevacizumab and 69% had received 1 previous line of treatment. Median follow-up was 28.9 months. The adjusted hazard ratio ...

International audience; The mucin MUC4 and its membrane partner the ErbB2 oncogenic receptor are potential interacting partners in human pancreatic tumour development. However, the way they function is still largely unknown. In this work, we aimed to identify the cellular mechanisms and the intracellular signalling pathways under the control of both ErbB2 and MUC4 in a human pancreatic adenocarcinomatous cell line. Using co-immunoprecipitation and GST pull-down, we show that MUC4 and ErbB2 interact in the human pancreatic adenocarcinomatous cell line CAPAN-2 via the EGF domains of MUC4. Stable cell clones were generated in which either MUC4 or ErbB2 were knocked down (KD) by a shRNA approach. Biological properties of these cells were then studied in vitro and in vivo. Our results show that ErbB2-KD cells are more apoptotic and less proliferative (decreased cyclin D1 and increased p27kip1 expression) while migration and invasive properties were not altered. MUC4-KD clones were less proliferative with decreased cyclin D1 expression, G1 cell cycle arrest and altered ErbB2/ErbB3 expression. Their migration properties were reduced whereas invasive properties were increased. Importantly, inhibition of ErbB2 and MUC4 expression did not impair the same signalling pathways (inhibition of MUC4 expression affected the JNK pathway whereas that of ErbB2 altered the MAPK pathway). Finally, ErbB2-KD and MUC4-KD cells showed impaired tumour growth in vivo. Our results show that ErbB2 and MUC4, which interact physically, activate different intracellular signalling pathways to regulate biological properties of CAPAN-2 pancreatic cancer cells.

On 28 July, 2009, on the occasion of his first speech as Chairman of the Chamber of Deputies, the Christian democrat Laurent Mosar stated that “70% of the bills adopted by the Chamber were related to European directives,” and that for this reason national MPs would have to be more involved in the whole European legislative process rather than acting only at transposition time. He recalled that the Lisbon Treaty would give national parliaments more means to do so, and wished to this end that the government would inform the assembly as swiftly as possible about preliminary legislative texts discussed at the European level.

Background The chemotherapy used to treat lung cancer causes febrile neutropenia in 10 to 40% of patients. Although most episodes are of undetermined origin, an infectious etiology can be suspected in 30% of cases. In view of the scarcity of data on lung cancer patients with febrile neutropenia, we performed a retrospective study of the microbiological characteristics of cases recorded in three medical centers in the Picardy region of northern France. Methods We analyzed the medical records of lung cancer patients with neutropenia (neutrophil count < 500/mm3) and fever (temperature > 38.3°C). Results The study included 87 lung cancer patients with febrile neutropenia (mean age: 64.2). Two thirds of the patients had metastases and half had poor performance status. Thirty-three of the 87 cases were microbiologically documented. Gram-negative bacteria (mainly enterobacteriaceae from the urinary and digestive tracts) were identified in 59% of these cases. Staphylococcus species (mainly S. aureus) accounted for a high proportion of the identified Gram-positive bacteria. Bacteremia accounted for 60% of the microbiologically documented cases of fever. 23% of the blood cultures were positive. 14% of the infections were probably hospital-acquired and 14% were caused by multidrug-resistant strains. The overall mortality rate at day 30 was 33% and the infection-related mortality rate was 16.1%. Treatment with antibiotics was successful in 82.8% of cases. In a multivariate analysis, predictive factors for treatment failure were age >60 and thrombocytopenia < 20000/mm3. Conclusion Gram-negative species were the most frequently identified bacteria in lung cancer patients with febrile neutropenia. Despite the success of antibiotic treatment and a low-risk neutropenic patient group, mortality is high in this particular population.

Understanding the formation of governments has always been central to political science. Traditionally this topic has been considered from a rational choice theory perspective and the empirical testing of these theories; however neither approach alone is able to explain a large proportion of actual coalition formations. This comparative volume brings together a rational choice theory perspective and the empirical testing of these theories to study government formation. It provides in-depth studies of government formations in Europe that cannot be accounted for by existing coalition theory in order to identify potential explanatory factors that have been neglected so far. These ‘coalition puzzles’ are reconstructed by country experts based on secondary sources, newspaper accounts, internal party documents, and interviews in an effort to understand why particular governments were formed. In conclusion, this book assesses whether new factors can be integrated into rational choice theories or whether these analyses point to the need for a different paradigm. This important volume will be of interest to students and scholars of political science, European politics and comparative politics.

Patrick Dumont, Lieven De Winter and Rudy Andeweg, “From coalition theory to coalition puzzles “ in Rudy B. Andeweg, Lieven De Winter and Patrick Dumont (eds.) Puzzles of Government Formation. Coalition theory and deviant cases, Routledge/ECPR studies in European political science, London, 2011, pp. 1-23

Caspases play a key role in the apoptotic pathway by virtue of their ability to cleave key protein substrates within the dying cell. Caspases are produced as inactive zymogens, and need to become proteolytically processed in order to become active. A key executioner caspase, caspase-3, has previously been found to exist in both the cytosol and the mitochondria. At the mitochondria, caspase-3 is associated with both the inner and outer mitochondrial membranes, where it interacts with heat shock proteins Hsp60 and Hsp10. Like caspase-3, a small portion of the p53 tumor suppressor protein is localized to mitochondria, particularly after genotoxic stress. p53 interacts with various members of the Bcl2 family at the mitochondria, and this interaction is key to its ability to induce apoptosis. In this study, we sought to determine the identity of other mitochondrial p53-interacting proteins. Using immunoprecipitation from purified mitochondria followed by mass spectrometry we identified caspase-3 as a mitochondrial p53-interacting protein. Interestingly, we find that tumor-derived mutant forms of p53 retain the ability to interact with mitochondrial caspase-3. Further, we find evidence that these mutant forms of p53 may interfere with the ability of procaspase-3 to become proteolytically activated by caspase-9. The combined data suggest that tumor-derived mutants of p53 may be selected for in tumor cells due to their ability to bind and inhibit the activation of caspase-3.

This paper is to describe a system for mobile position reporting of mobiles and remote monitoring (short data messaging). It is based on the use of small satellites (mass The main features of the system are the low development and user costs as well as the worldwide and high capacity capabilities (more than 500 000 mobile terminals per geographical zone). Such a system is economically attractive for companies managing large mobile fleets. It is well suited for a ponctual utilization when real time is not needed.

1. Introduction: Setting a New Agenda for Research - Francoise Boucek and Matthijs Bogaards PART I: Concepts and Measures 2. Rethinking Dominant Party Systems - Patrick Dunleavy 3. Measuring One-Party Dominance with Voting Power Indices - Jean-Francois Caulier and Patrick Dumont 4. District-Level Dominance and Vulnerability under the French Fifth Republic - Nicolas Sauger PART II: Cases and Comparisons i: Sub-national Dominance 5. Big Fish in Small Ponds: A Comparison of Dominant Parties in the Canadian Provinces and German Lander - Amir Abedi and Steffen Schneider 6. Hard and Soft Dominance: Assessing the Case of the Bavarian CSU - Gordon Smith ii: The Intra-Party Dimension of Dominance 7. The Factional Politics of Dominant Parties: Evidence from Britain, Italy and Japan - Francoise Boucek 8. Dominance without Factions: The Liberal Party of Canada - R. Kenneth Carty iii: Dominance and Democracy 9. A Resource Theory of Single Party Dominance: The PRI in Mexico - Kenneth F. Greene 10. One-Party Dominance in South-Africa - James Myburgh and Hermann Giliomee 11. Laying a Foundation for Democracy or Undermining It? Dominant Parties in Africa's Burgeoning Democracies - Staffan I. Lindberg and Jonathan Jones 12. Conclusion - Francoise Boucek and Matthijs Bogaards

1. Structural and Strategic Factors Affecting the Hiring and Firing of Ministers 2. Hiring and Firing Ministers under Informal Constraints: Germany 3. Cabinet Dynamics and Ministerial Careers in the French Fifth Republic 4. Choosing, Moving and Resigning at Westminster 5. Italy: the Difficult Road towards a more Effective Process of Ministerial Selection 6. Cabinet Dynamics in Democratic Spain 7. Ups and Downs of Ministerial Careers in a Partitocratic Federal State 8. Portugal: The Primacy of 'Independents' 9. In Tranquil Waters: Swedish Cabinet Ministers in the Post-War Era 10. Constructing and Maintaining Irish Governments 11. More Safe than Sound? Cabinet Ministers in Iceland 12. Learning to Rule: Ministerial Careers in Post-Communist Democracies

Pea3 and Erm are transcription factors expressed in normal developing branching organs such as the mammary gland. Deregulation of their expression is generally associated with tumorigenesis and particularly breast cancer. By using RNA interference (RNAi) to downregulate the expression of Pea3 and/or Erm in a mammary cancer cell line, we present evidence for a role of these factors in proliferation, migration and invasion capacity of cancer cells. We have used different small interfering RNAs (siRNAs) targeting pea3 and erm transcripts in transiently or stably transfected cells, and assessed the physiological behavior of these cells in in vitro assays. We also identified an in vivo alteration of tumor progression after injection of cells that overexpress pea3 and/or erm short hairpin RNAs (shRNAs) in immunodeficient mice. Using transcriptome profiling in Pea3- or Erm-targeted cells, two largely independent gene expression programs were identified on the basis of their shared phenotypic modifications. A statistically highly significant part of both sets of target genes had previously been already associated with the cellular signaling pathways of the ;proliferation, migration, invasion' class. These data provide the first evidence, by using endogenous knockdown, for pivotal and complementary roles of Pea3 and Erm transcription factors in events crucial to mammary tumorigenesis, and identify sets of downstream target genes whose expression during tumorigenesis is regulated by these transcription factors., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

quels sont les élements d'importance pour une section locale.

From the conditioned medium of the human colon carcinoma cells, HT-29 5M21 (CM-5M21), expressing a spontaneous invasive phenotype, tumor-associated trypsin inhibitor (TATI) was identified and characterized by proteomics, cDNA microarray approaches and functional analyses. Both CM-5M21 and recombinant TATI, but not the K18Y-TATI mutant at the protease inhibitor site, trigger collagen type I invasion by several human adenoma and carcinoma cells of the colon and breast, through phosphoinositide-3-kinase, protein kinase C and Rho-GTPases/Rho kinase-dependent pathways. Conversely, the proinvasive action of TATI in parental HT29 cells was alleviated by the TATI antibody PSKAN2 and the K18Y-TATI mutant. Stable expression of K18Y-TATI in HT-29 5M21 cells downregulated tumor growth, angiogenesis and the expression of several metastasis-related genes, including CSPG4 (13.8-fold), BMP-7 (9.7-fold), the BMP antagonist CHORDIN (5.2-fold), IGFBP-2 and IGF2 (9.6- and 4.6-fold). Accordingly, ectopic expression of KY-TATI inhibited the development of lung metastases from HT-29 5M21 tumor xenografts in immunodeficient mice. These findings identify TATI as an autocrine transforming factor potentially involved in early and late events of colon cancer progression, including local invasion of the primary tumor and its metastatic spread. Targeting TATI, its molecular partners and effectors may bring novel therapeutic applications for high-grade human solid tumors in the digestive and urogenital systems.

Von 1945 bis heute teilt das Luxemburger Parteiensystem alle Merkmale von Sartoris „moderate pluralism“ (Sartori 1976, S. 173). Samtliche Regierungen dieses Zeitraums bestanden aus Koalitionen, und die zentristische Tendenz des gesamten politischen Feldes begunstigte die am starksten zentristische Partei (Christlich-Soziale Volkspartei - CSV), welche abwechselnd in Koalition mit den Sozialisten (Letzebuerger Sozialistesch Arbechterpartei - LSAP) oder den Liberalen (Demokratesch Partei - DP) regierte. Die geringe ideologische Distanz zwischen den Parteien ermoglichte jedoch das Zustandekommen verschiedener Zweierkoalitionen (CSV-LSAP, CSV-DP, aber auch DP-LSAP von 1974 bis 1979).

In addition to a well-defined transcriptional activity that is necessary for efficient apoptosis induction, the p53 tumor suppressor also has a direct apoptogenic role at the mitochondria. This direct role in cell death is mediated at least in part by interaction of p53 with BCL2 family members, including the pro-apoptotic protein BAK. Whereas it is currently accepted that the mitochondrial function of p53 contributes to its tumor suppressive role, the regulation of p53 function at this organelle is poorly understood. In this manuscript we examine the role of p53 oligomerization in the regulation of its pro-apoptotic function at the mitochondria, specifically in regard to its ability to induce BAK oligomerization. We find that deletion or mutation of p53's oligomerization domain markedly impairs the ability of this protein to oligomerize BAK. Along these lines, cross-linking studies indicate that the majority of p53 localized to mitochondria is in dimeric or higher-order oligomeric form. In support of the importance of the p53-BAK interaction in the localization of p53 to mitochondria, we find that mouse embryo fibroblasts from the BAK null mouse have greatly reduced mitochondrial p53 compared to wild type fibroblasts. These data indicate that pro-apoptotic BAK, unlike other BCL2 family members, may serve as a major receptor for p53 on the mitochondria.

Our study has shown that the Amaryllidaceae isocarbostyril narciclasine induces marked apoptosismediated cytotoxic effects in human cancer cells but not in normal fibroblasts by triggering the activation of the initiator caspases of the death receptor pathway (caspase-8 and caspase-10) at least in human MCF-7 breast and PC-3 prostate carcinoma cells. The formation of the Fas and death receptor 4 (DR4) death-inducing signaling complex was clearly evidenced in MCF-7 and PC-3 cancer cells. Caspase-8 was found to interact with Fas and DR4 receptors on narciclasine treatment. However, narciclasine-induced downstream apoptotic pathways in MCF-7 cells diverged from those in PC-3 cells, where caspase-8 directly activated effector caspases such as caspase-3 in the absence of any further release of mitochondrial proapoptotic effectors. In contrast, in MCF-7 cells, the apoptotic process was found to require an amplification step that is mitochondria-dependent, with Bid processing, release of cytochrome c, caspase-9 activation. It is postulated that the high selectivity of narciclasine to cancer cells might be linked, at least in part, to this activation of the death receptor pathway. Normal human fibroblasts appear approximately 250-fold less sensitive to narciclasine, which does not induce apoptosis in these cells probably due to the absence of death receptor pathway activation.

TPS8110 Background: The incidence of lung cancer is increasing dramatically in women and displays some specific epidemiological, radiological, clinical and pathological characteristics. Two main me...

e19110 Background: In the last few years, new drugs and strategies have emerged in the management of lung cancer (LC). ESCAP-2011-CPHG, promoted by the French College of General Hospital Respirator...

Preface Chapter 1. Delegation in Contemporary Democracies: introduction (Dietmar Braun and Fabrizio Gilardi PART 1: THE STANDARD CHAIN OF DELEGATION Chapter 2. The (Moral) Hazards of Parliamentary Democracy (Kaare Strom, Wolfgang C. Muller, Torbjorn Bergman) Chapter 3. Delegation and Accountability in Parliamentary Democracies: Smallness, Proximity and Shortcuts (Patrick Dumont and Frederic Varone) Chapter 4. A Theory of Efficient Delegation (David Epstein and Sharyn O'Halloran) Chapter 5. A Delegation Theory for Explaining the Bureaucratization of Public Administrations (Victor Lapuente Gine) PART 2: THE NEXT STEPS OF DELEGATION: INDEPENDENT AGENCIES, INTEREST ORGANIZATIONS, AND THE EUROPEAN UNION Chapter 6. Delegation to Independent Regulatory Agencies in Western Europe: Credibility, Political Uncertainty, and Diffusion (Fabrizio Gilardi) Chapter 7. Delegation in the distributive policy arena: the case of research policy (Dietmar Braun) Chapter 8. Consequences of Legitimising Independent Regulatory Agencies in Contemporary Democracies: Theoretical Scenarios Chapter 9. Whose Agents? Non-Governmental Organisations in Policy-Proposing Commissions: Agents of Government or Opposition Parties? (Peter Munk Christiansen & Asbjorn Sonne Norgaard) Chapter 10. Delegation in the European Union: Debates and Research Agenda (Fabio Franchino) CONCLUSION Chapter 11. Delegation in Contemporary Democracies: Concluding Remarks (Dietmar Braun and Fabrizio Gilardi)

This paper confronts two models of policy: the party model states that policy-making is an orderly process initiated by parties implementing their party programme and carrying out their electoral promises; the external pressure model contends that policy change is a non-orderly process but rather a disjoint process coming in large bursts that are difficult to predict. Drawing upon eight policy agendas in Belgium covering the period from 1991 to 2000 we put both models to the test. Policy measures are operationalized via the budget and legislation. We found that budgets are as good as disconnected from any other policy agenda in Belgium. Legislation and the evolving legislative attention for issues in Belgium can be traced back to some extent to parties and external pressure at the same time. In terms of static policy priorities, we found that the party model indicators, party programmes and government agreements, are fairly good predictors of the legislative attention an issue will receive during the governmental term. Regarding dynamic policy change from year to year, we found that the external pressure indicators – parliamentary pressure, media coverage and street protest – performed much better and were able to grasp some variance in issue emphasis in legislation.

In addition to a common polymorphism at codon 72, the p53 tumor suppressor gene also contains a rare single nucleotide polymorphism at amino acid 47. Wild type p53 encodes proline at this residue, but in

The tumour suppressor activity of the p53 protein has been explained by its ability to induce apoptosis in response to a variety of cellular stresses1,2. Thus, understanding the mechanism by which p53 functions in the execution of cell death pathways is of considerable importance in cancer biology. Recent studies have indicated that p53 has a direct signalling role at mitochondria in the induction of apoptosis3,4,5,6, although the mechanisms involved are not completely understood. Here we show that, after cell stress, p53 interacts with the pro-apoptotic mitochondrial membrane protein Bak. Interaction of p53 with Bak causes oligomerization of Bak and release of cytochrome c from mitochondria. Notably, we show that formation of the p53–Bak complex coincides with loss of an interaction between Bak and the anti-apoptotic Bcl2-family member Mcl1. These results are consistent with a model in which p53 and Mcl1 have opposing effects on mitochondrial apoptosis by interacting with, and modulating the activity of, the death effector Bak.

There is substantial evidence in the literature that, in addition to functioning as an activator of transcription, the p53 tumor suppressor protein can also function as a sequence-specific transcriptional repressor of a separate set of genes. However, elucidation of the mechanism whereby p53 functions as a transcriptional repressor has been obscured by the use of artificial assays to measure this activity; these assays include transient transfection analyses, where both p53 and target promoters are overexpressed. This chapter describes alternative approaches for the definition of sequence elements that mediate transcriptional repression by p53. These include the McKay (immunobinding) assay, which measures the in vitro binding of large fragments of DNA, as well as chromatin immunoprecipitations (ChIPs), which measure in vivo binding. The use of such assays should better define the mechanism of transcriptional repression by p53 and should aid in the elucidation of the contribution of this activity to p53-dependent growth arrest and programmed cell death (apoptosis).