Integrated genomic characterization of endometrial carcinoma

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

Jean Baptiste Francois Pompallier, Thomas Arnold and Julian Edmund Tenison Woods and their contribution to the formation and development of Catholic schooling in Australasia

Histories of Catholic education have received little attention by Church historians and are usually written by members of the Catholic clergy, with a strong emphasis placed on the spiritual and building accomplishments of the bishops. This thesis examines the provision of Catholic Education in Australasia, with a focus on the contribution of three men, Jean Baptiste Francois Pompallier, Thomas Arnold and Julian Edmund Tenison Woods. These men received support from the female religious orders in the regions where they worked, frequently with little recognition or praise by Catholic Church authorities. The tenets of their faith gave Pompallier and Woods strength and reinforced their determination to succeed. Arnold, however, possessed a strong desire to change society. All three believed in the desirability of providing Catholic schooling for the poor, with the curriculum facilitating the acquisition of socially desirable values and traits, including obedience, honesty, moral respectability and a strong adherence to Catholic religious values. The beneficiaries included society, future employers, the Church, the children and their parents. With the exception of promoting distinctly Catholic religious values, Roman Catholic schools and National schools in Australasia shared identical objectives. Historians have neglected the contributions of these men.

Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer

OBJECTIVES: Four randomized phase II/III trials investigated the addition of cetuximab to platinum-based, first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). A meta-analysis was performed to examine the benefit/risk ratio for the addition of cetuximab to chemotherapy. MATERIALS AND METHODS: The meta-analysis included individual patient efficacy data from 2018 patients and individual patient safety data from 1970 patients comprising respectively the combined intention-to-treat and safety populations of the four trials. The effect of adding cetuximab to chemotherapy was measured by hazard ratios (HRs) obtained using a Cox proportional hazards model and odds ratios calculated by logistic regression. Survival rates at 1 year were calculated. All applied models were stratified by trial. Tests on heterogeneity of treatment effects across the trials and sensitivity analyses were performed for all endpoints. RESULTS: The meta-analysis demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival (HR 0.88, p=0.009, median 10.3 vs 9.4 months), progression-free survival (HR 0.90, p=0.045, median 4.7 vs 4.5 months) and response (odds ratio 1.46, p<0.001, overall response rate 32.2% vs 24.4%) compared with chemotherapy alone. The safety profile of chemotherapy plus cetuximab in the meta-analysis population was confirmed as manageable. Neither trials nor patient subgroups defined by key baseline characteristics showed significant heterogeneity for any endpoint. CONCLUSION: The addition of cetuximab to platinum-based, first-line chemotherapy for advanced NSCLC significantly improved outcome for all efficacy endpoints with an acceptable safety profile, indicating a favorable benefit/risk ratio.

An Interview with Sylvère Lotringer, Jean Baudrillard Chair at the European Graduate School and Professor Emeritus of French Literature and Philosophy at Columbia University, on the Architectural Contribution to Semiotext(e), Schizoculture, and the Early Deleuze and Guattari Scene at Columbia University

An Interview with Sylvère Lotringer, Jean Baudrillard Chair at the European Graduate School and Professor Emeritus of French Literature and Philosophy at Columbia University, on the Architectural Contribution to Semiotext(e), Schizoculture, and the Early Deleuze and Guattari Scene at Columbia University, which took place at the Department of French, Columbia University, New York City, July 2003. This interview exists as an audio cassette tape recording.

The idea of women : representations of power in the work of Charles Bukowski

This thesis is a comparative textual analysis of Charles Bukowski's representations of power in relation to the idea of women. The exegesis explores Bukowski's idea of women and power as exemplified by the representational differences between his short stories for Hustler Magazine and his novel Women. The creative piece, a novel, "Many a Broken Hearted Woman" informed and was informed by this research.

Imaginative cinematic geographies of Australia : the mapped view in Charles Chauvel's Jedda and Baz Luhrmann's Australia

Cinema is central to the mediation of history and the construction of imaginative geographies that offer a politicized view of the land and its people. This article investigates cinematic representations of landscape and analyses the ways in which maps and journeys in Charles Chauvel’s film Jedda (1955) and Baz Luhrmann’s Australia (2008)—both set in the far North of Australia—articulate conceptions of “Australianness” in relationship to Indigeneity and the land. We argue the exotic tropics and arid outback regions of northern Australia function metonymically as representative of the nation in these films, working to naturalize ideological values and affirm dominant narratives of history, identity, and entitlement.

The Jean Chretien Pledge to Africa act: Patent law and humanitarian aid

This article evaluates the implementation of the WTO General Council Decision in 2003, which resolved that developed nations could export patented pharmaceutical drugs to member states in order to address public health issues - such as HIV/AIDS, tuberculosis, malaria and other epidemics. The Jean Chretien Pledge to Africa Act 2004 (Canada) provides authorisation for the export of pharmaceutical drugs from Canada to developing countries to address public health epidemics. The European Union has issued draft regulations governing the export of pharmaceutical drugs. A number of European countries - including Norway, the Netherlands, France, and Switzerland - are seeking to pass domestic legislation to give force to the WTO General Council Decision. Australia has shown little initiative in seeking to implement such international agreements dealing with access to essential medicines. It is argued that Australia should implement humanitarian legislation to embody the WTO General Council Decision, emulating models in Canada, Norway, and the European Union. Ideally, there should be no right of first refusal; the list of pharmaceutical drugs should be open-ended; and the eligible importing countries should not be limited to members of the WTO.

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10−4, Bonferroni corrected), of which six reached P < 5 × 10−8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5–89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.

At the Limits of Presentation : Coming-into-Presence and its Aesthetic Relevance in Jean-Luc Nancy's Philosophy

This study investigates the significance of art in Jean-Luc Nancy s philosophy. I argue that the notion of art contributes to some of Nancy s central ontological ideas. Therefore, I consider art s importance in its own right whether art does have ontological significance, and if so, how one should describe this with respect to the theme of presentation. According to my central argument, with his thinking on art Nancy attempts to give one viewpoint to what is called the metaphysics of presence and to its deconstruction. On which grounds, as I propose, may one say that art is not reducible to philosophy? The thesis is divided into two main parts. The first part, Presentation as a Philosophical Theme, is a historical genesis of the central concepts associated with the birth of presentation in Nancy s philosophy. I examine this from the viewpoint of the differentiation between the ontological notions of presentation and representation by concentrating on the influence of Martin Heidegger and Jacques Derrida, as well as of Hegel and Kant. I give an overview of the way in which being or sense for Nancy is to be described as a coming-into-presence or presentation . Therefore, being takes place in its singular plurality. I argue that Nancy redevelops Heidegger s account of being in two principal ways: first, in rethinking the ontico-ontological difference, and secondly, by striving to radicalize the Heideggerian concept of Mitsein, being-with . I equally wish to show the importance of Derrida s notion of différance and its inherence in Nancy s questioning of being that rests on the unfoundedness of existence. The second part, From Ontology to Art, draws on the importance of art and the aesthetic. If, in Nancy, the question of art touches upon its own limit as the limit of nothingness, how is art able to open its own strangeness and our exposure to this strangeness? My aim is to investigate how Nancy s thinking on art finds its place within the conceptual realm of its inherent difference and interval. My central concern is the thought of originary ungroundedness and the plurality of art and of the arts. As for the question of the difference between art and philosophy, I wish to show that what differentiates art from thought is the fact that art exposes what is obvious but not apparent, if apparent is understood in the sense of givenness. As for art s ability to deconstruct Nancy s ontological notions, I suggest that in question in art is its original heterogeneity and diversity. Art is a matter of differing art occurs singularly, as a local difference. With this in mind, I point out that in reflecting on art in terms of spacing and interval, as a thinker of difference Nancy comes closer to Derrida and his idea of différance than to the structure of Heidegger s ontological difference.

Rajamerkkien vartijat : Maariidat Helsingin ja Sipoon pitäjissä 1630 - 1669

Tutkielman aiheena ovat säätyläisten ja talonpoikien maariidat Helsingin ja Sipoon pitäjissä 1600-luvun puolessa välissä. Historiallisen kriminologian tutkijat ovat pitäneet kiinteään maaomaisuuteen liittyneitä maariitoja keskeisenä syynä 1500-luvun korkeaan väkivallan tasoon. 1600-luvulla väkivalta kutistui pieneksi rikosryhmäksi alioikeuksien alkaessa toimia. Enää talonpoikien ei tarvinnut turvautua väkivaltaan omaisuutta puolustaessaan, vaan riidat saatiin päätökseen käräjillä. Tässä työssä selvitän Helsingin ja Sipoon tuomiokirjojen avulla, mitä tapahtui maariidoille 1600-luvulla, sillä itse maariidat ovat jääneet väkivaltatutkimuksen varjoon historiallisessa kriminologiassa. Arvioin maariitoja kvantitatiivisesti ja kvalitatiivisesti syventyen erityisesti niiden yleisyyteen, osapuoliin, maariitojen rooliin talonpoikien ja säätyläisten elämässä sekä maariitojen 1600-luvulle tyypillisiin piirteisiin. Lahjoitusmaat lisääntyivät etenkin 1630- ja 1640-luvuilla voimakkaasti Suomessa. Myös pienaatelin asuttamissa Sipoon ja Helsingin pitäjissä aateliset laajensivat maaomistuksiaan talonpoikaismaan kustannuksella. Baltiasta ja Keski-Euroopasta Suomeen saapuneet feodaaliset omistuskäsitykset asettivat aateliset ja talonpojat törmäyskurssille. Maariitojen käsittely oikeudessa oli siviiliprosessi, jossa periaatteessa tasa-arvoiset osapuolet ottivat yhteen riita-asiassa. Omaisuusriitojen käsittelyssä säilyi huomattavan pitkään perinteisiä, paikallisia, tapaoikeuden piirteitä, joita kruunu oli pyrkinyt karsimaan pois muista rikosasioiden käsittelyistä. Perinteiset oikeustavat eivät kuuluneet modernisoituvan ja keskittyvän valtion oikeusjärjestelmään. Ne säilyivät kuitenkin omaisuusoikeuteen liittyvissä maariidoissa huomattavan pitkään, koska riidanratkaisun auktoriteetti oli laajalla alalla käräjäyhteisössä. Maariidat olivat Helsingin ja Sipoon pitäjissä 4. suurin rikosryhmä 1600-luvun puolessa välissä. Niitä voidaankin pitää agraarisen yhteiskunnan tyyppirikoksena. Säätyläisten suuri määrä osapuolten joukossa oli 1600-luvun maariidoille tyypillinen piirre. Oikeus oli tasapuolinen säätyjä kohtaan arvioidessaan tapausten syyllisyyskysymystä, mutta asettui selvästi säätyläisten puolelle jaellessaan rangaistuksia. Säätyläisiä rangaistiin maariidoissa lievällä vahingonkorvauksella ja talonpoikia yleensä ankarammalla sakolla. Väkivallalla oli maariidoissa keskeinen rooli myös 1600-luvulla. Etenkin 1630-luvulla väkivaltaa esiintyi lähes kaikissa maariidoissa. 1640-luvulla oikeus vakiinnutti asemansa maariitojen ratkaisuareenana väkivallan sijaan ja riidat ratkaistiin käräjätuvassa. Silti väkivallan rooli maariitojen taustalla säilyi. Joka viidennen maariidan taustalla oli väkivaltaa. Tyypillisintä se oli talonpoikien välisissä maariidoissa. Väkivalta sai hyvin raakojakin piirteitä maariitojen yhteydessä. Lievästä väkivallasta oli kyse vain harvoin. Vuosikausia kestäneet maariitojen kierteet saivat päätöksensä 1600-luvun puolessa välissä oikeuden saavuttaessa riittävästi valtaa pitääkseen annetut tuomiot voimassa myös maariidoissa. Suurimmassa osassa Helsingin ja Sipoon pitäjien maariidoista saatiin päätös ensimmäisellä käräjäkerralla tai alle vuoden kuluessa riidan puhkeamisesta. Kuitenkin 17 prosenttia riidoista oli pitkään jatkuneita riitoja, joista oli riidelty yli vuosi. Oikeuteen luotettiin enemmän ja se pystyi pitämään tuomiot voimassa toisin kuin vielä 1500-luvulla. Talonpojat yhdistivät usein voimansa aatelisia vastaan käydyissä maariidoissa. Heidän keskuuteensa vaikutti syntyneen moraalinen yhteisö aatelin talonpoikaiselle maanomistukselle muodostamaa uhkaa vastaan. Toisiaan vastaan riidellessä solidaarisuus oli tiessään. Tasavahvojen osapuolten oli tultava toimeen omillaan. Säätyläiset turvautuivat maariitoihin lähinnä taloudellisten syiden vuoksi. Kun kartano ei kannattanut, alustalaisten tai rajapiiritilojen maita saattoi yrittää saada haltuunsa viemällä riita käräjille jopa tekaistun syyn varjolla. Kyseenalaistamalla vanhat rajat heillä oli tarkoitus saada omiin maihin lisää alaa ja siten saada uutta maata rälssiksi. Etenkin oman rälssimaan rajojen sisäpuolella aatelisilla oli vahva usko oikeudestaan toimia tahtonsa mukaan omistuksillaan huolimatta siitä, oliko kyseessä perintötila vai lampuodin tila.

'The ones with the beastly lives': Gender and textuality in Jean Rhys's Voyage in the Dark

Anna Morgan, the central character of Jean Rhys's Voyage in the Dark, has previously been read as a victim of her own inability to fashion some form of life for herself.1 It is possible, however, to suggest an alternative to such character-based readings and instead examine the systems of oppression which work to ensure that Anna remains an excluded, marginalized subject. Rather than personal failings, it is Anna's gender and colonial status which prevent her from participating fully in the dominant social and economic order of Voyage in the Dark. Anna is textually constrained on three levels, which may be defined as economic, colonialist, and narrative. Imbricated within these is the question of gender, which functions to place Anna in a position of double-exclusion within the text. These forms of exclusion function at the levels of discourse and narrative; I would argue that Anna's position is not, therefore, a product of realist character 'flaws' but rather that her discursive placement within the novel offers insight into the ways in which colonialism and sexism function in terms of textuality.

Francine and Jean-Pierre Durand at Aenny Catzenstein's 80th birthday; London Portraits Family

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Jean-Pierre Durand, Patrick Matthiesen, unidentified woman and Serge Donabedian working on a puzzle at Aenny's 80th birthday; London.

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