Soft tissue sarcoma: biology and therapeutic correlates

Soft tissue sarcomas (STS) comprise a heterogenenous group of greater than 50 malignancies of putative mesenchymal cell origin and as such they may arise in diverse tissue types in various anatomical locations throughout the whole body. Collectively they account for approximately 1% of all human malignancies yet have a spectrum of aggressive behaviours amongst their subtypes. They thus pose a particular challenge to manage and remain an under investigated group of cancers with no generally applicable new therapies in the past 40 years and an overall 5-year survival rate that remains stagnant at around 50%. From September 2000 to July 2006 I undertook a full time post-doctoral level research fellowship at the MD Anderson Cancer Center, Houston, Texas, USA in the department of Surgical Oncology to investigate the biology of soft tissue sarcoma and test novel anti- sarcoma adenovirus-based therapy in the preclinical nude rat model of isolated limb perfusion against human sarcoma xenografts. This work, in collaboration with colleagues as indicated herein, led to a number of publications in the scientific literature furthering our understanding of the malignant phenotype of sarcoma and reported preclinical studies with wild-type p53, in a replication deficient adenovirus vector, and oncolytic adenoviruses administered by isolated limb perfusion. Additional collaborative and pioneering preclinical studies reported the molecular imaging of sarcoma response to systemically delivered therapeutic phage RGD-4c AAVP. Doxorubicin chemotherapy is the single most active broadly applicable anti-sarcoma chemotherapeutic yet only has an approximate 30% overall response rate with additional breakthrough tumour progression and recurrence after initial chemo-responsiveness further problematic features in STS management. Doxorubicin is a substrate for the multi- drug resistance (mdr) gene product p-glycoprotein drug efflux pump and exerts its main mode of action by induction of DNA double-strand breaks during the S-phase of the cell cycle. Two papers in my thesis characterise different aspects of chemoresistance in sarcoma. The first shows that wild-type p53 suppresses Protein Kinase Calpha (PKCα) phosphorylation (and activation) of p-glycoprotein by transcriptional repression of PKCα through a Sp-1 transcription factor binding site in its -244/-234 promoter region. The second paper demonstrates that Rad51 (a central mediator of homologous recombination repair of double strand breaks) has elevated levels in sarcoma and particularly in the S- G2 phase of the cell cycle. Suppression of Rad51 with small interfering RNA in sarcoma cell culture led to doxorubicin chemosensitisation. Reintroduction of wild-type p53 into STS cell lines resulted in decreased Rad51 protein and mRNA expression via transcriptional repression of the Rad51 promoter through increased AP-2 binding. In light of poor response rates to chemotherapy, escape from local control portends a poor prognosis for patients with sarcoma. Two papers in my thesis characterise aspects of sarcoma angiogenesis, invasion and metastasis. Human sarcoma samples were found to have high levels of matrix metalloproteinase-9 (MMP-9) with expression levels that correlated with p53 mutational status. MMP-9 is known to degrade extracellular collagen, contribute to the control of the angiogenic switch necessary in primary tumour progression and facilitate invasion and metastasis. Reconstitution of wild-type p53 function led to decreased levels of MMP-9 protein and mRNA as well as zymography-assessed MMP-9 proteolytic activity and decreased tumour cell invasiveness. Reintroduction of wild-type p53 into human sarcoma xenografts in-vivo decreased tumour growth and MMP-9 protein expression. Wild-type p53 was found to suppress mmp-9 transcription via decreased binding of NF-κB to its -607/-595 mmp-9 promoter element. Studies on the role of the VEGF165 in sarcoma found that sarcoma cells stably transfected with VEGF165 formed more aggressive xenografted tumours with increased vascularity, growth rate, metastasis, and resistance to chemotherapy. Use of the anti-VEGFR2 antibody DC101 enhanced doxorubicin sensitivity at sub-conventional dosing, inhibited tumour growth, decreased development of metastases, and reduced tumour micro-vessel density while increasing the vessel maturation index. These effects were explained primarily through effects on endothelial cells (e.c.s), rather than the tumour cells per se, where DC101 induced e.c. sensitivity to doxorubicin and suppressed e.c. production of MMPs. The p53 tumour suppressor pathway is the most frequently mutated pathway in sarcoma. Recapitulation of wild-type p53 function in sarcoma exerts a number of anti-cancer outcomes such as growth arrest, resensitisation to chemotherapy, suppression of invasion, and attenuation of angiogenesis. Using a modified nude rat-human sarcoma xenograft model for isolated limb perfusion (ILP) delivery of wild-type p53 in a replication deficient adenovirus vector I showed that functionally competent wild-type p53 could be delivered to and detected in human leiomyosarcoma xenografts confirming preclinical feasibility - although not efficacious due to low transgene expression. Viral fibre modification to express the RGD tripeptide motif led to greater viral uptake by sarcoma cells in vitro (transductional targeting) and changing the transgene promoter to a response element active in cells with active telomerase expression restricted the transgene expression to the tumour intracellular environment (transcriptional targeting). Delivery of the fibre-modified, selectively replication proficient oncolytic adenovirus Ad.hTC.GFP/ E1a.RGD by ILP demonstrated a more robust, and tumour-restricted, transgene expression with evidence of anti-sarcoma effect confirmed microscopically. Collaborative studies using the fibre modified phage RGD-4C AAVP confirmed that systemic delivery specifically, efficiently, and repeatedly targets human sarcoma xenografts, binds to αv integrins in tumours, and demonstrates a durable, though heterogeneous, transgene expression of 1-4 weeks. Incorporation of the Herpes Simplex Virus thymidine kinase (HSVtk) transgene into RGD-4C AAVP permitted CT-PET spatial and temporal molecular imaging in vivo of transgene expression and allowed quantification of tumour metabolic activity both before and after interval administration of a systemic cytotoxic with predictable and measurable response to treatment before becoming apparent clinically. These papers further the medical and scientific community’s understanding of the biology of soft tissue sarcoma and report preclinical studies with novel and promising anti- sarcoma therapeutics.

Tempo atmosférico numa perspetiva CTS através do ensino por pesquisa

O ser Humano, desde sempre tem tentado estabelecer relações entre si, o tempo e o clima, de modo a melhorar as suas condições de vida. Atualmente existem questões problema que ameaçam a humanidade, nomeadamente as alterações climáticas e o aquecimento global com vista à promoção de um Desenvolvimento Sustentável. À educação é atribuída extrema importância no desenvolvimento de uma adequada perceção da situação do planeta. Este facto levou as Nações Unidas a proclamarem, no início deste século (dezembro de 2002), a Década da Educação para o Desenvolvimento Sustentável. Um desafio internacional lançado aos países para que recorram à educação como ferramenta essencial na promoção do Desenvolvimento Sustentável. A vida nas sociedades contemporâneas é extremamente influenciada pelos desenvolvimentos científicos e tecnológicos, dependendo dos seus respetivos progressos. Como tal, a Educação Científica assume um papel fundamental na compreensão das problemáticas que o ser Humano enfrenta, assim como na sua própria consciencialização da responsabilidade na situação planetária atual. Devendo promover o desenvolvimento de cidadanias proactivas, fundamentadas e responsáveis, no sentido da mudança, numa perspetiva crítica global que garanta a sustentabilidade do planeta. Estes factos são alvo de reflexão por parte de diversas instâncias da sociedade tais como a UNESCO, comunidades nacionais e internacionais de investigação em Educação Científica, e o poder político que se espelham em propostas de reforma e de revisão curricular em diversos países. Neste contexto, a Escola, como instituição formal de Educação, toma o papel primordial de promover o Desenvolvimento Sustentável através da aquisição de conhecimentos, atitudes, valores e competências que permitam desenvolver nos alunos uma consciencialização ecológica e uma literacia científica. Com este propósito em mente surge a questão investigativa deste estudo “Como Abordar o Tempo Atmosférico numa Perspetiva CTS Através do Ensino Por Pesquisa?”. Assim, usando o laboratório mais acessível e gratuito, a Atmosfera, e recursos facilmente acessíveis para desenvolver atividades simples é apresentada uma proposta de abordagem em sala de aula para a temática “Tempo Atmosférico” em particular a “Previsão e Descrição do Tempo Atmosférico”. A Atmosfera é um fascinante laboratório de ensino, porque nela se podem estudar alguns processos físicos lecionados ao longo dos mais variados níveis de ensino nas disciplinas de Física, Química e Geografia. Na Atmosfera, podem realizar-se diversos estudos simples, que de uma forma fácil respondem a inquietantes questões relacionadas com a Previsão e Descrição do Tempo Atmosférico. Neste estudo foi desenvolvida e usada uma metodologia para construir e interpretar mapas de tempo permitindo a alunos do 3º Ciclo do Ensino Básico fazer a Previsão e Descrição do Tempo Atmosférico. Após a aplicação da estratégia para o desenvolvimento de capacidades, de criatividade, envolvimento, cidadania e de pensamento crítico, os alunos responderam a um questionário. Através do tratamento dos dados obtidos pode-se considerar que em média 97% dos alunos consideram importante ou muito importante o estudo desta temática e que tem influência no seu dia-a-dia. Verificou-se que em média, se passou de 26% de respostas cientificamente corretas ou parcialmente corretas para 83% de respostas cientificamente corretas ou parcialmente corretas, o que demostra que a estratégia proposta atingiu os seus propósitos que passavam por dinamizar e fomentar uma cultura meteorológica nas escolas e para as escolas. Salienta-se a importância da possibilidade do trabalho em rede e das suas potencialidades na motivação dos alunos dada a oportunidade de fazer diagnóstico do tempo atmosférico local e inter-regiões. Os alunos consultaram e interpretaram mapas de tempo atmosférico, usaram a Internet e compreendam a relação e a influência entre diferentes parâmetros meteorológicos. Os resultados obtidos neste estudo permitem afirmar que os alunos desenvolveram competências numa área que é uma preocupação de cada um, o diagnóstico do tempo atmosférico. Cresceu neles uma cultura meteorológica e as aprendizagens nesta temática podem transbordar para colegas, amigos, pais e toda a comunidade escolar. Assim pode considerar-se que a estratégia implementada foi promotora de mudança, de aquisição de conhecimentos e do desenvolvimento de competências numa temática tão aliciante que envolve o Desenvolvimento Sustentável. Considera-se ainda que a estratégia usada neste estudo é motivadora, aliada à dinâmica CTS e ao Ensino Por Pesquisa, com vista a ser utilizada em contexto de sala de aula. Este estudo é uma forte contribuição para o Ensino das Ciências em especial no ensino da temática Tempo Atmosférico e é uma ferramenta importante que pode e deve ser utilizada em contexto escolar pois está escrito de modo a ser consultado por profissionais de ensino, nomeadamente pelos professores de Física, Química e de Geografia de modo a promoverem o desenvolvimento de competências de literacia científica e de cidadania e contribuir para a formação de futuros cidadãos ativos e conscientes defensores da Sustentabilidade da Terra.

Equality of opportunity and equality of outcome

The report on the findings of extensive empirical research on equality of educational opportunities carried out in the US on a very large sample of public schools by Coleman and his colleagues has had a major impact on education policy and has given rise to a large amount of research and various interpretations. However, as some interpreters have highlighted, even more important than the findings of the survey themselves has been Coleman’s redefinition of equality of opportunity, abandoning the then prevailing conception of equality of educational opportunities as equality of starting points and replacing it with the concept of equality of educational opportunities as equality of educational outcomes. The question is, therefore, whether equality of outcomes really is one of the two types of equality of opportunity. The purpose of the present article is to show that equality of opportunity and equality of outcomes are two different types of equality. If they are different, the interpretation that Coleman has redefined the concept of “equality of educational opportunity” turns out to be incorrect. (DIPF/Orig.)

Bogusław Śliwa (1944-1989) - działacz opozycji demokratycznej i "Solidarności" w Kaliszu

Bogusław Śliwa was born in Lvov on 6 October 1944. He graduated in law studies at Adam Mickiewicz University in Poznań in 1969. Following the completion of his prosecutor’s apprenticeship he worked, among others, in Wolsztyn, Świebodzin and – from 1975 – in Kalisz. On 22 August 1978 Śliwa was fired from the public prosecutor’s office because he had attempted to detect a person who murdered during the robbery committed by a Civic Militia officer. That time he established and maintained close contacts with activists of the Workers’ Defence Committee (KOR), among others: Jacek Kuroń, Mirosław Chojecki, Adam Michnik, Bronisław Geremek, Jan Lityński, Zofia Romaszewska and Zbigniew Romaszewski. In 1978 he began to cooperate with the Kalisz group of the Movement for the Defence of Human and Civil Rights (ROPCiO). In the early 1979 this group started to publish “Wolne Słowo” in which Śliwa was a co-editor. On 28 June 1979 in Poznań he was involved in founding the Social Self-Defence Club of the Wielkopolska and Kujawy Region. In September 1980, during strikes at the FWR “Runotex” and KZKS “Winiary” in Kalisz Śliwa was an expert representing the workers. On 29 September of that year, he arranged in Kalisz a meeting of representatives and delegates of enterprises in Kalisz aimed at appointing the Board of the Inter-Enterprise Founding Committee of the Independent Self-Governing Trade Union. He became the secretary. Bogusław Śliwa also engaged in setting up and developing an information team. He was informally responsible for developing an information and printing base. Bogusław Śliwa set up “NSZZ Solidarność” magazine where he published his own articles. He also founded the “Solidarność” Workers’ Community Centre in Kalisz. it is noteworthy that it was the only community centre in Poland established by „Solidarność”. In December the Nationwide Liaison Commission of „Solidarność” appointed him to the Committee for the Defence of Prisoners of Conscience established on 10 December of that year. He participated in the information meeting of the Independent Self-Governing Trade Union of Independent Farmers “Solidarność Wiejska” held in Staw, in Szczytniki commune. During that meeting “Solidarność Wiejska” led by Mieczysław Walczykiewicz requested the authorities to liquidate the “Świt” Agricultural Production Cooperative in Cieszyków, in Szczytniki commune. Bogusław Śliwa was involved in this successful event. It was the first liquidation of cooperative in Poland. On 11 January 1981 Śliwa co-organized the 1st Regional Convention of „Solidarność” Wiejska in Kalisz. Following the so-called Bydgoszcz events of 19 March 1981 he advocated the general strike. Due to his attitude, Śliwa was listed as one of 146 „Solidarność” activists executed by the 3rd “A” Department of the Ministry of Internal Affairs. According to the authorities those activists presented radical views. On 30 June 1981 at the 1st General Delegates Convention of the Kaliskie province, Śliwa, as a delegate of the Kaliskie province, was appointed to the Regional Board of „Solidarność” – Southern Wielkopolska. In July Śliwa set up in Kalisz the underground branch of the Polish Democratic Party. In 1981 Śliwa was a delegate to the 1st National Delegates Convention of „Solidarność” and co-edited with Jan Lityński the document entitled: “Message to the Working People of Eastern Europe” originated by Henryk Siciński and adopted by the 1st National Delegates Convention. On 22 November he participated in the Warsaw-held meeting founding the Self-Governing Republic Clubs “Liberty – Equality– Independence” and signed the founding declaration. On 28 of that month he co-organized with Antoni Pietkiewicz a founding meeting of the Club in Kalisz. When martial law was declared he began to hide in Kalisz. Śliwa was arrested on 25 February 1982 and interned in Ostrów Wielkopolski and then in Gębarzew and Kwidzyn. After being released on 25 November 1982, he was immediately involved in the activity of the underground movement of „Solidarność”. He edited the first two issues of “Nasza Solidarność” magazine published in Kalisz. Śliwa co-invented and co-organized the 1st May march that was independent from the authorities’ one held in Kalisz in 1983. Consequently, he was temporarily arrested and detained in Ostrów Wielkopolski. On 7 June 1983 he was released from custody. The amnesty declared on 21 July 1983 caused that the investigation against him was discontinued. In July of the same year he co-founded the Inter-Regional Coordination Commission of the Independent Self-Governing Trade Union “Solidarność” Kalisz-Konin-Sieradz. As he could not find any work and he and his family were exposed to psychological harassment, he emigrated to Sweden on 30 December 1983. He worked, among other positions, as bookbinder. He was the board secretary of the Congress of Poles in Sweden. In 1984 he commented the death of priest Jerzy Popiełuszko in “Dagens Nyheter” daily. He was also interviewed by Radio Liberty. Śliwa commenced cooperating with representatives of the „Solidarność” Coordination Office in Paris, Brussels and Stockholm. On 18 April 1985 the Military Garrison Prosecutor’s Office in Wrocław initiated investigations against Śliwa, charging him with activities detrimental to political interests of the People’s Republic of Poland. Subsequently, on 10 July 1985 this public prosecutor’s office decided to issue an arrest warrant for him. On the same day the public prosecutor suspended criminal proceedings against him. In December 1985, after the courageous escape of two brothers, Adam and Krzysztof Zieliński, from Poland to Sweden, he helped them prevent their deportation and stay in their new homeland. He expressed his opinion on this issue on Swedish television and in “ Dagens Nyheter” daily. His intervention helped them legally stay in Sweden. In 1989 he arrived in Poland. During this short visit he met and talked with his colleagues from the so-called first „Solidarność”. Bogusław Śliwa died in Stockholm on 23 November 1989. He was buried there on 7 December 1989. On 18 October 2006 he was posthumously honoured by Lech Kaczynski, President of Poland, with the Order of Polonis Restitution. On 15 June 2007 Bogusław Śliwa was posthumously granted the title of an Honorary Citizen of Kalisz by the Town Council of Kalisz.

É preciso ter coragem: um estudo das narrativas de mulheres na política

É na busca por compreender a inserção e participação de mulheres na política partidária na contemporaneidade que esta dissertação, situada na linha de pesquisa Culturas, Linguagens e Utopias, tem como objetivo analisar as narrativas de vereadoras de municípios que estão localizados na região sul do Rio Grande do Sul no período de 2009-2012. O corpus de análise constitui-se de entrevistas individuais semiestruturadas com as onze vereadoras participantes a partir da metodologia de investigação narrativa. Partindo das contribuições dos Estudos Culturais e de Gênero em suas vertentes pós-estruturalistas procurou-se problematizar alguns discursos e práticas que emergiram nas narrativas com base nas contribuições da análise do discurso de Michel Foucault. Assim, verificou-se que a representação cultural das mulheres neste campo político está fundamentada em concepções essencialistas do gênero feminino como a sensibilidade. Isso vem provocando discussões na ciência política e nos estudos de gênero a partir de termos como política de ideias, política de desvelo que discutem a presença das mulheres em decorrência ou não desses atributos. O fato é que esses discursos vêm instituindo diferenças na participação de homens e mulheres na política e constituindo formas de ser mulher na política partidária e de fazer política diferenciada das dos homens de forma menos “dura”, “rígida”. Ao debruçar-se na inserção das mulheres nessa esfera pública constatou-se uma trajetória marcada pelas noções de público e privado que impediu ao longo de nossa história a participação das mulheres no campo político e o desenvolvimento de sua cidadania. Além disso, nas narrativas das vereadoras fica evidente que as mulheres não foram constituídas para participarem do que hoje é um direito seu: a esfera pública de decisão da política. Isso foi constatado a partir do convite que foi feito para a candidatura pelos partidos que a partir das cotas partidárias procuraram mais significativamente por mulheres para concorrer. Também se observou neste estudo o capital político de ingresso das mulheres nessa esfera: o capital familiar, capital dos movimentos sociais e capital de ocupação em cargos públicos. Quanto a participação das mulheres no cotidiano de seus mandatos identificamos a dificuldade de ser mulher e política na atualidade. As negociações com os partidos e os colegas, a conciliação entre a família e a vida pública; os focos de atuação dedicados as áreas sociais e nesse destacamos mais significativamente a educação. Por fim, o que pretendemos foi desconfiar da máxima “lugar de mulher não é na política” e conhecer as trajetórias e histórias de mulheres que cotidianamente entre conflitos e disputas lutam pelo seu lugar na esfera pública, pelo exercício de sua cidadania.

Prevenção de úlceras por pressão segundo a perspectiva do enfermeiro intensivista

Analisar a atuação dos enfermeiros de unidade de terapia intensiva na prevenção da úlcera por pressão. Método: trata-se de estudo descritivo desenvolvido com 13 enfermeiros da unidade de terapia intensiva do Hospital Universitário Onofre Lopes (HUOL), em Natal-RN. Foi aplicado um questionário, submetido à análise de conteúdo temática. O estudo foi aprovado pelo Comitê de Ética da Universidade Federal do Rio Grande do Norte (UFRN), sob o CAAE n. 0240.0.051.000-10. Resultados: os enfermeiros reportaram a realização da mudança de decúbito, a avaliação de risco, a discussão com os colegas sobre as medidas adotadas, a higiene e hidratação da pele do paciente através de uso de ácidos graxos essenciais e hidratante corporal, o cuidado com a disposição dos lençóis, de forma a evitar dobras, a utilização de colchão de ar e a aplicação de placas de hidrocoloide nas proeminências ósseas. Conclusão: a prática da prevenção das úlceras por pressão aplicada pelos enfermeiros da unidade de terapia intensiva ocorre sem padronização dos cuidados